Fluid exchange apparatus for expandable port delivery system and methods of use

ABSTRACT

A device for injecting a therapeutic agent into an ocular implant at least partially implanted in an eye including an injection lumen providing a pathway for injecting the therapeutic agent into the implant; an outlet lumen providing a pathway for pre-existing fluid in the ocular implant to exit the implant; and a collection chamber fluidly coupled to the outlet lumen that provides a first fluid outflow resistance and a second fluid outflow resistance. The first fluid outflow resistance is lower than a first resistance to outflow of the implant. The second fluid outflow resistance is greater than a force imparted onto the implant by intraocular pressure of the eye. Injection of therapeutic agent into the implant via the injection lumen causes the pre-existing fluid to exit the implant and enter the collection chamber via the outlet lumen and causes a second pre-existing fluid to displace from the collection chamber.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of co-pending U.S. application Ser.No. 16/877,308, filed May 18, 2020, which is continuation and claimspriority to PCT/US2018/061262 filed on Nov. 15, 2018, and claimspriority to U.S. Provisional Patent Application Ser. No. 62/589,377,filed Nov. 21, 2017, entitled “Fluid Exchange Apparatus for ExpandablePort Delivery System and Methods of Use,” the disclosures of which arehereby incorporated by reference in their entirety for all purposes.

BACKGROUND

Diseases that affect vision can be treated with a variety of therapeuticagents, but the delivery of drugs to the eye continues to bechallenging. Injections of therapeutic via the eye can be painful,involve some risk of infection, hemorrhage and retinal detachment.Depending on the frequency, intra-ocular injections can betime-consuming for both patient and physician. Consequently, in at leastsome instances the drug may be administered less often than theprescribed frequency resulting in sub-optimal treatment benefit.Further, bolus intra-ocular injections may not provide the idealpharmacokinetics and pharmacodynamics. A bolus injection of drug intothe vitreous humor of a patient can result in a peak drug concentrationseveral times higher than the desired therapeutic amount and then beforethe patient is able to get the next injection drop to a drugconcentration that is far below therapeutic effectiveness.

SUMMARY

In an aspect, described is a device for injecting a therapeutic agentinto an ocular implant, the implant being at least partially implantedin an eye, the implant further providing at least a first resistance tooutflow of therapeutic agent into the eye. The device includes aninjection lumen configured to provide a pathway for injecting thetherapeutic agent into the ocular implant; an outlet lumen configured toprovide a pathway through which pre-existing fluid in the ocular implantexits the ocular implant; and a collection chamber fluidly coupled tothe outlet lumen. The collection chamber is configured to receive thepre-existing fluid that exits the ocular implant via the outlet lumen.The collection chamber provides a first fluid outflow resistance and asecond fluid outflow resistance. The first fluid outflow resistance islower than the first resistance to outflow of the implant, and thesecond fluid outflow resistance is greater than a force imparted ontothe implant by intraocular pressure of the eye. Injection of therapeuticagent into the ocular implant via the injection lumen causes thepre-existing fluid to exit the ocular implant and enter the collectionchamber via the outlet lumen and causes a second pre-existing fluid todisplace from the collection chamber.

The implant can be expandable once implanted in the eye from a first,collapsed configuration to a second, enlarged configuration. A firstporous structure operatively coupled to the collection chamber canprovide the first fluid outflow resistance and the second fluid outflowresistance. The first porous structure operatively coupled to thecollection chamber can have the first fluid outflow resistance to gasoutflow and the second fluid outflow resistance to liquid outflow. Theimplant can include a second porous structure that provides the firstresistance to outflow. The first fluid outflow resistance of the firstporous structure of the collection chamber can be less than the firstresistance provided by the second porous structure of the implant. Thesecond fluid outflow resistance of the first porous structure of thecollection chamber can be greater than the first resistance of theimplant. The second pre-existing fluid can be a gas. The gas can be air.The air can be under vacuum. The second pre-existing fluid can bedisplaced from the collection chamber via a vent. The secondpre-existing fluid can be displaced from the collection chamber via avalve. The implant can be expandable once implanted in the eye from afirst, collapsed configuration to a second, enlarged configuration. Thefirst porous structure of the collection chamber can prevent collapse ofthe implant away from the second, enlarged configuration after filling.

The first porous structure of the collection chamber can be ahydrophobic membrane, a fabric, a porous fabric, a semipermeablemembrane, an air permeable material, a moisture vapor transferwaterproof fabric, a hydrophilic porous material, or a porous sinteredmaterial. The first porous structure of the collection chamber can bepositioned within an annular element positioned near an upper end of thecollection chamber. The annular element can form a fixed upper limit ofthe collection chamber. The collection chamber can be concentric with alongitudinal axis of the injection lumen. The collection chamber can beoffset relative to a longitudinal axis of the injection lumen. Thecollection chamber can be tubular. The collection chamber can extendbetween an opening into the tubular collection chamber and terminate atthe second porous structure. The tubular structure can have a uniforminner diameter over a length of the tubular structure. The tubularstructure can have an inner diameter that enlarges proximally to asecond inner diameter. The tubular structure can be coiled. The coiledtubular structure can provide a uniform fill pattern that minimizestrapping of the second pre-existing fluid displaced from the collectionchamber.

In some variations, one or more of the following can optionally beincluded in any feasible combination in the above methods, apparatus,devices, and systems. More details of the devices, systems, and methodsare set forth in the accompanying drawings and the description below.Other features and advantages will be apparent from the description anddrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other aspects will now be described in detail with referenceto the following drawings. Generally speaking the figures are not toscale in absolute terms or comparatively but are intended to beillustrative. Also, relative placement of features and elements may bemodified for the purpose of illustrative clarity.

FIG. 1 is a cross-sectional, schematic view of a portion of the humaneye;

FIG. 2 is a partial, cross-sectional, schematic view of a portion of theeye having an implementation of a therapeutic device at least partiallyimplanted within the sclera of the eye along an axis of insertion A;

FIG. 3 is a partial, cross-sectional, schematic view of a portion of theeye having another implementation of a therapeutic device at leastpartially implanted within the sclera of the eye along an axis ofinsertion A;

FIGS. 4 and 5 are partial, cross-sectional, schematic views of a portionof the eye having another implementation of a therapeutic device atleast partially implanted within the sclera of the eye along an axis ofinsertion A;

FIG. 6 is a cross-sectional view of the therapeutic device of FIG. 5 ;

FIGS. 7 and 8 are cross-sectional views of the therapeutic device ofFIG. 5 ;

FIG. 9 is a top down view of the therapeutic device of FIG. 5 ;

FIG. 10 is a cross-sectional view of another implementation of atherapeutic device having an implementation of a flow director;

FIG. 11 is a cross-sectional view of another implementation of atherapeutic device having another implementation of a flow director;

FIG. 12 is a cross-sectional view of another implementation of atherapeutic device;

FIG. 13 is a partial, cross-sectional perspective view of animplementation of a flange element on a therapeutic device;

FIGS. 14A-14D illustrate sequential views of a generic tool inserted tofill a therapeutic device;

FIG. 15 is an implementation of an exchange needle apparatus forrefilling of an implanted therapeutic device;

FIG. 16 is a detail view of an elongate structure of the apparatus ofFIG. 15 ;

FIG. 17 is a cross-sectional view of an elongate structure showing asheath extending over a needle;

FIGS. 18A-18C illustrate an implementation of an exchange apparatushaving a locking connector to couple to a syringe;

FIG. 18D is an implementation of an elongate structure and receivercontainer of the exchange apparatus of FIG. 18A;

FIG. 18E illustrates various sheath configurations;

FIGS. 19A-19C illustrate collapse of expandable reservoir walls duringfluid exchange and loss of payload due to intraocular pressure;

FIGS. 20A-20C illustrate fluid exchange with the exchange needleapparatus of FIG. 18B preventing collapse of expandable reservoir andpayload loss;

FIG. 21 illustrates an implementation of an exchange apparatus having agenerally concentric collection chamber;

FIG. 22 illustrates an implementation of an exchange apparatus having anoff-set collection chamber;

FIG. 23 illustrates an implementation of an exchange apparatus having anoff-set collection chamber;

FIGS. 24A-24D illustrate various views of an implementation of anexchange apparatus having an off-set collection chamber;

FIG. 25 illustrates an implementation of an exchange apparatus having anoffset collection chamber designed for larger capacity;

FIGS. 26A-26C illustrate an implementation of an exchange apparatushaving a removable collection chamber; and

FIGS. 27A-27D are another implementation of an exchange apparatus havinga removable collection chamber.

It should be appreciated that the drawings are for example only and arenot meant to be to scale. It is to be understood that devices describedherein may include features not necessarily depicted in each figure.

DETAILED DESCRIPTION

Described herein are implantable devices, systems and methods of use forthe delivery of one or more therapeutics for the treatment of diseasesand methods and apparatus to exchange a fluid of the implantable device.

The devices and systems described herein maximize reservoir volume andcapacity while minimizing overall device invasiveness and impact on eyeanatomy and vision. In some implementations, the devices describedherein include an expandable reservoir that can be compressed into afirst configuration for minimally-invasive delivery into the eye, forexample, through the sclera and expanded into a second, enlargedconfiguration upon filling with therapeutic agent following implantationin the eye. When in the second configuration, the reservoir can avoidinterfering with the visual axis of the eye as well as remain a safedistance away from certain anatomical structures of the eye so as toavoid damage and impacting vision. As will be described herein, in someimplementations the expandable reservoir in the expanded configurationtakes on a shape that is eccentric, asymmetrical, or otherwise off-setfrom the axis of placement of the device into the eye tissue, forexample an axis of insertion through the sclera. This off-set can resultin a majority of the expanded volume of the reservoir being directedaway from certain critical structures of the anterior segment of theeye, for example, the lens, the ciliary body, the choroid, as well asthe sclera and surrounding internal tissue layers through which thedevice was inserted. The expandable reservoir in the expandedconfiguration can also remain symmetrical or coaxial with a central axisof the device, but can be shaped such that at least a portion of thedevice is curved, angled, or otherwise off-set relative to the axis ofinsertion. For example, the expanded reservoir can be shaped into an arcor other curvilinear shape relative to the axis of insertion.Alternatively, the expanded reservoir can be shaped to form an anglerelative to the axis of insertion. In these implementations, the overalllength of the device can be increased while still remaining outside thevisual axis or significantly impacting the visual field. These and otherfeatures of the devices described herein will be described in moredetail below.

After an amount of time, the fluid of the implantable device may bereplaced exchanged, or the device otherwise refilled to provideadditional amounts of therapeutic agent to extend the therapy. Describedherein are apparatus and methods to place therapeutic fluids in a devicealready implanted in the eye. The apparatus provides improved samplingand replacement of the fluid with optimum exchange efficiency, little orno leakage resulting from the pressure of the injection, and aclinically acceptable exchange time.

It should also be appreciated that the devices and systems describedherein can be positioned in many locations of the eye and need not beimplanted specifically as shown in the figures or as described herein.The devices and systems described herein can be used to delivertherapeutic agent(s) for an extended period of time to one or more ofthe following tissues: intraocular, intravascular, intraarticular,intrathecal, pericardial, intraluminal and intraperitoneal. Althoughspecific reference is made below to the delivery of treatments to theeye, it also should be appreciated that medical conditions besidesocular conditions can be treated with the devices and systems describedherein. For example, the devices and systems can deliver treatments forinflammation, infection, and cancerous growths. Any number of drugcombinations can be delivered using any of the devices and systemsdescribed herein.

The materials, compounds, compositions, articles, and methods describedherein may be understood more readily by reference to the followingdetailed description of specific aspects of the disclosed subject matterand the Examples included therein. Before the present materials,compounds, compositions, articles, devices, and methods are disclosedand described, it is to be understood that the aspects described beloware not limited to specific methods or specific reagents, as such mayvary. It is also to be understood that the terminology used herein isfor the purpose of describing particular aspects only and is notintended to be limiting.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the invention(s) belong. All patents, patent applications,published applications and publications, websites and other publishedmaterials referred to throughout the entire disclosure herein, unlessnoted otherwise, are incorporated by reference in their entirety. In theevent that there are pluralities of definitions for terms herein, thosein this section prevail. Where reference is made to a URL or other suchidentifier or address, it is understood that such identifiers can changeand particular information on the internet can come and go, butequivalent information is known and can be readily accessed, such as bysearching the internet and/or appropriate databases. Reference theretoevidences the availability and public dissemination of such information.

As used herein, relative directional terms such as anterior, posterior,proximal, distal, lateral, medial, sagittal, coronal, transverse, etc.are used throughout this disclosure. Such terminology is for purposes ofdescribing devices and features of the devices and is not intended to belimited. For example, as used herein “proximal” generally means closestto a user implanting a device and farthest from the target location ofimplantation, while “distal” means farthest from the user implanting adevice in a patient and closest to the target location of implantation.

As used herein, a disease or disorder refers to a pathological conditionin an organism resulting from, for example, infection or genetic defect,and characterized by identifiable symptoms.

As used herein, treatment means any manner in which the symptoms of acondition, disorder or disease are ameliorated or otherwise beneficiallyaltered. Treatment also encompasses any pharmaceutical use of thedevices described and provided herein.

As used herein, amelioration or alleviation of the symptoms of aparticular disorder, such as by administration of a particularpharmaceutical composition, refers to any lessening, whether permanentor temporary, lasting or transient that can be attributed to orassociated with administration of the composition.

As used herein, an effective amount of a compound for treating aparticular disease is an amount that is sufficient to ameliorate, or insome manner reduce the symptoms associated with the disease. Such anamount can be administered as a single dosage or can be administeredaccording to a regimen, whereby it is effective. The amount can cure thedisease but, typically, is administered in order to ameliorate thesymptoms of the disease. Repeated administration can be required toachieve the desired amelioration of symptoms. Pharmaceutically effectiveamount, therapeutically effective amount, biologically effective amountand therapeutic amount are used interchangeably herein to refer to anamount of a therapeutic that is sufficient to achieve a desired result,i.e. Therapeutic effect, whether quantitative or qualitative. Inparticular, a pharmaceutically effective amount, in vivo, is that amountthat results in the reduction, delay, or elimination of undesirableeffects (such as pathological, clinical, biochemical and the like) inthe subject.

As used herein, sustained release encompasses release of effectiveamounts of an active ingredient of a therapeutic agent for an extendedperiod of time. The sustained release may encompass first order releaseof the active ingredient, zero order release of the active ingredient,or other kinetics of release such as intermediate to zero order andfirst order, or combinations thereof. The sustained release mayencompass controlled release of the therapeutic agent via passivemolecular diffusion driven by a concentration gradient across a porousstructure.

As used herein, a subject includes any animal for whom diagnosis,screening, monitoring or treatment is contemplated. Animals includemammals such as primates and domesticated animals. An exemplary primateis human. A patient refers to a subject such as a mammal, primate,human, or livestock subject afflicted with a disease condition or forwhich a disease condition is to be determined or risk of a diseasecondition is to be determined.

As used herein, a therapeutic agent referred to with a trade nameencompasses one or more of the formulation of the therapeutic agentcommercially available under the tradename, the active ingredient of thecommercially available formulation, the generic name of the activeingredient, or the molecule comprising the active ingredient. As usedherein, therapeutic or therapeutic agents are agents that ameliorate thesymptoms of a disease or disorder or ameliorate the disease or disorder.Therapeutic agent, therapeutic compound, therapeutic regimen, orchemotherapeutic include conventional drugs and drug therapies,including vaccines, which are known to those skilled in the art anddescribed elsewhere herein. Therapeutic agents include, but are notlimited to, moieties that are capable of controlled, sustained releaseinto the body.

As used herein, a composition refers to any mixture. It can be asolution, a suspension, an emulsion, liquid, powder, a paste, aqueous,non-aqueous or any combination of such ingredients.

As used herein, fluid refers to any composition that can flow. Fluidsthus encompass compositions that are in the form of semi-solids, pastes,solutions, aqueous mixtures, gels, lotions, creams and other suchcompositions.

As used herein, a kit is a packaged combination, optionally, includinginstructions for use of the combination and/or other reactions andcomponents for such use.

Eye Anatomy

FIG. 1 is a cross-sectional, schematic view of a portion of the humaneye 10 showing the anterior chamber, posterior chamber and vitreous bodyof the eye. The eye 10 is generally spherical and is covered on theoutside by the sclera 24. The bulk of the eye 10 is filled and supportedby the vitreous body 30 (referred to herein as vitreous humor or justvitreous), a clear, jelly-like substance disposed between the lens 22and the retina 26. The retina 26 lines the inside posterior segment ofthe eye 10 and includes the macula 32. The retina 26 registers the lightand sends signals to the brain via the optic nerve. The fovea centralisis the part of the eye located in the center of the macula 32 of theretina 26 and is the region responsible for sharp central vision, forexample in order to read or drive. An imaginary line passing from themidpoint of the visual field to the fovea centralis is called the visualaxis 27. The hypothetical straight line passing through the centers ofcurvature of the front and back surfaces of the lens 22 is the opticaxis 29.

The elastic lens 22 is located near the front of the eye 10. The lens 22provides adjustment of focus and is suspended within a capsular bag fromthe ciliary body 20, which contains the muscles that change the focallength of the lens 22. A volume in front of the lens 22 is divided intotwo by the iris 18, which controls the aperture of the lens 22 and theamount of light striking the retina 26. The pupil is a hole in thecenter of the iris 18 through which light entering anteriorly passes.The volume between the iris 18 and the lens 22 is the posterior chamber.The volume between the iris 18 and the cornea 12 is the anteriorchamber. Both chambers are filled with a clear liquid known as aqueoushumor.

The cornea 12 extends to and connects with the sclera 24 at a locationcalled the limbus 14 of the eye. The conjunctiva 16 of the eye isdisposed over the sclera 24 and the Tenon's capsule extends between theconjunctiva 16 and the sclera 24. The eye 10 also includes a vasculartissue layer called the choroid 28 that is disposed between a portion ofthe sclera 24 and the retina 26. The ciliary body 20 is continuous withthe base of the iris 18 and is divided anatomically into pars plica andpars plana 25, a posterior flat area approximately 4 mm long.

The devices described herein can be positioned in many locations of theeye 10, for example in the pars plana region away from tendon of thesuperior rectus muscle and one or more of posterior to the tendon,anterior to the tendon, under the tendon, or with nasal or temporalplacement of the therapeutic device. As shown in FIG. 2 , the devicesdescribed herein can be positioned along an axis of insertion A throughthe sclera 24 in the pars plana region and expanded such that the deviceavoids interfering with the visual field, and in particular, the visualand optic axes 27, 29.

Surgical placement of trans-scleral ocular implants designed topenetrate the globe such that certain regions of the implant occupysupra-scleral, trans-scleral, sub-scleral, and intravitreal aspects ofthe ocular anatomy in the pars plana region involves a risk of acutevitreous hemorrhage (VH) following surgery. The devices described hereinincorporate one or more features that mitigate the risk of vitreoushemorrhage at the time of surgical implantation and lead to improvedhealing following surgery.

Treatment Devices

The devices described herein are referred to as drug delivery devices,treatment devices, therapeutic devices, port delivery systems, and thelike. It should be appreciated that these terms are used interchangeablyherein and are not intended to be limiting to a particularimplementation of device over another. The devices and systems describedherein can incorporate any of a variety of features described herein andthe elements or features of one implementation of a device and systemdescribed herein can be incorporated alternatively or in combinationwith elements or features of another implementation of a device andsystem described herein as well as the various implants and featuresdescribed in U.S. Pat. Nos. 8,399,006; 8,623,395; PCT Pat. PublicationNo. WO 2012/019136; PCT Pat. Publication No. WO 2012/019047; PCT Pat.Publication No. WO 2012/065006; U.S. Publication No. 2016/0128867; andU.S. Provisional Application Ser. No. 62/318,582. For the sake ofbrevity, explicit descriptions of each of those combinations may beomitted although the various combinations are to be considered herein.For example, the devices described herein can include non-rigid walledreservoirs configured to enlarge following implantation such as byfilling with treatment solution. The expandable reservoirs describedherein may be used with any of the various implementations of a deviceor system. Further, reference to an expandable reservoir can include areservoir wall that is pliable and able to be folded, compressed,contracted, etc. into a low profile configuration that is suitable forinsertion into the eye in a manner that minimizes the size ofpenetration. The wall of an expandable reservoir may be pliable orflexible, but need not be stretchy or elastomeric in order to enlarge insize to hold the treatment solution. The expandable reservoir caninclude a reservoir wall that tents, unfolds, expands, stretches, orotherwise enlarges the overall cross-sectional size of the reservoircompared to the low profile configuration suitable for insertion. Itshould be appreciated that the terms unfold, expand, enlarge, and otherterms used to refer to this shape change of the reservoirs describedherein may be used interchangeably.

Additionally, described herein are different methods for implantationand access of the devices. The various implants can be implanted,removed, filled, refilled, aspirated, and/or flushed, etc. according toa variety of different methods and using a variety of different devicesand systems. Provided are some representative descriptions of how thevarious devices may be implanted and accessed, however, for the sake ofbrevity explicit descriptions of each method with respect to eachimplant or system may be omitted.

The porous structures (also referred to herein as a drug releasemechanism, drug release element, release control element, RCE, or frit)as described herein can be used with a number of various differentimplantable therapeutic devices including one or more of those devicesdescribed U.S. Pat. Nos. 8,399,006; 8,623,395; PCT Pat. Publication No.WO 2012/019136; PCT Pat. Publication No. WO 2012/019047; and PCT Pat.Publication No. WO 2012/065006; the entire disclosures of which areincorporated herein by reference thereto.

FIGS. 2 and 3 as well as FIGS. 4-9 illustrate implementations of anexpandable treatment device 100 configured to deliver one or moretherapeutic agents to one or more regions of the eye 10. The device 100can include a proximal retention structure 105 having a smoothprotrusion or flange element 110, a porous drug release element 120, andan expandable reservoir 130. An access port 111 can extend through theretention structure 105 and a penetrable element 115 can be positionedwithin at least a portion of the access port 111. The penetrable element115 and the access port 111 allow for access to an inner volume of thereservoir 130, for example, to fill, refill, aspirate, and/or flushmaterials in the reservoir 130. In some implementations, the access port111 can be formed by an opening through the retention structure 105 intothe reservoir 130 and covered by a penetrable material and/or thepenetrable element 115. The penetrable element 115 can be a septumconfigured to be penetrated and resealed such that material does notleak out of the reservoir 130 following penetration of the materialduring in situ refilling of the reservoir 130. Alternatively, one ormore regions of the flange element 110 itself can be formed of apenetrable material.

The drug release element 120 can be positioned in a variety of locationswithin the device 100 such that the volume of the reservoir 130 is influid communication with the drug release element 120. For example, thedrug release element 120 can be positioned near a distal end region ofthe device 100 such as within an outlet 125 of the device 100, forrelease of the one or more therapeutic agents contained within thereservoir 130 into the eye. The drug release element 120 can also bepositioned in a region of the device proximal of the distal end region.The drug release element 120 can also be positioned towards a particulararea to be treated, such as the retina.

The device 100 can be implanted in the eye such that at least a portionof the device 100, for example the reservoir 130, the drug releaseelement 120 and one or more outlets 125, are positioned intraocularly.In some implementations, the device 100 can be positioned so as toextend through the sclera 24 from the pars plana region so as to releasethe therapeutic agent into the vitreous body 30. As mentioned above, thedevice 100 can be positioned in the eye along an axis of insertion A(see FIG. 6 ). The flange element 110 can form a smooth protrusionconfigured for placement along the sclera 24. The flange element 110 canremain generally external to the eye to aid in retention of the device100 while the remainder of the device 100 is at least partiallypositioned intraocularly. The flange element 110 can have any of avariety of shapes, for example, oval, ovoid, elliptical, circular, orother shape as will be discussed in more detail below. In someimplementations, the flange element 110 can be generally curved so as tohave a contour along a surface of a sphere. An outer-facing surface 112of the flange element 110 can have a convex shape and an inner-facingsurface 113 can have a concave shape such that the flange element 110can better conform to the curvature of the eye. In otherimplementations, the flange element 110 can be generally flat. The edgesof the flange element 110 can be generally smooth and rounded. In someimplementations, when the flange element 110 is positioned such that theinner-facing surface 113 of the flange element 110 can contact thesclera 24 and the outer-facing surface 112 of the flange element 110 canbe positioned under the conjunctiva 16 (not shown in FIG. 6 ) such thatthe conjunctiva 16 covers the outer-facing surface 112 of the flangeelement 110 and protects the therapeutic device 100. The conjunctiva 16covering the outer-facing surface 112 of the flange element 110 canallow access to the device 100 while decreasing the risk of infection tothe patient. When the therapeutic agent is inserted or injected into thedevice 100 through the access port of the flange element 110, theconjunctiva 16 may be lifted away, incised, or punctured with a needleto access the therapeutic device 100.

As best shown in FIGS. 7 and 8 , the retention structure 105 can includethe proximal flange element 110 as well as a neck positioned adjacentthe flange element 110. The neck can include a proximal region 116 and adistal extension 117. The proximal region 116 of the neck can be sizedalong a cross-section to fit a penetration site through the sclera 24,such as an incision and/or a puncture. For example, the proximal region116 can be narrowed relative to the flange element 110 to fit moresnugly within the penetration site in the sclera 24. FIG. 7 shows afirst cross-sectional view of the narrowed proximal region 116 of theneck. FIG. 8 shows a second cross-sectional view of the narrowedproximal region 116 of the neck taken along a plane orthogonal to thefirst cross-sectional view. The proximal region 116 of the neck can havea first cross-sectional distance across when taken along a first planeand a second cross-sectional distance across when the cross-section istaken along a second, orthogonal plane and the first cross-sectionaldistance can be different from the second cross-sectional distance. Thedistance across the proximal region 116 of the neck is shorter in theview of FIG. 7 (minor axis) compared to the distance across the proximalregion 116 of the neck in the view of FIG. 8 (major axis). In someimplementations, the cross-sectional shape of the proximal region 116 ofthe neck can complement a shape of the incision, puncture or otherpenetration site through which the device 100 is inserted. Thecross-sectional shape of the proximal region 116 of the neck can beelongated, including but not limited to one of a lentoid, oval, andellipse shape. In some implementations, the cross-sectional shape of theproximal region 116 of the neck is a first curve along a first axis anda second curve along a second axis that is different from the firstcurve. U.S. Pat. No. 8,277,830 and also U.S. Provisional ApplicationSer. No. 62/318,582, filed Apr. 5, 2016, which are incorporated byreference herein in their entirety, describes further details regardingthe geometry of the proximal region of the devices described herein. Itshould be appreciated that the dimensions of the neck or trans-scleralregion of the devices described herein can vary as well be described inmore detail below.

As mentioned above, the neck of the retention structure 105 can alsoinclude a distal extension 117. The distal extension 117 of the neck canextend inside the eye a distance away from the inner surface of thesclera 24 at the penetration site. As described above and as best shownin FIG. 6 , the flange element 110 can form a smooth protrusionconfigured for placement along the sclera 24. The proximal portion 116of the neck can fit within the penetration site of the sclera 24 suchthat the tissue being penetrated is received snugly within the proximalportion 116 of the neck. The distal extension 117 can be arrangedcoaxial with the insertion axis A of the device and can extend adistance away from the proximal portion 116.

The distal extension 117 of the neck can provide stabilization to thepenetrable region of the device 100 while eliminating contact betweenthe expandable reservoir 130 and inner surfaces of the eye adjacent theproximal end of the device 100. FIG. 2 shows an implementation of adevice 100 having a reservoir 130 that in the expanded configurationmakes contact with one or more internal surfaces of the eye adjacent theproximal end of the device 100. The proximal end of the reservoir 130can wedge against the internal tissue surfaces surrounding thepenetration site through the sclera 24 and can act to stabilize thepenetrable region of the device 100. In some implementations, contactbetween the reservoir 130 and the internal tissue surfaces is preventedto avoid irritation and/or damage of the delicate tissues of the eye.For example, as shown in FIG. 3 , the proximal end of the reservoir 130in the expanded configuration can be separated or off-set a distance D′from one or more internal tissue surfaces surrounding the penetrationsite. The distal extension 117 of the neck can aid in preventing contactbetween portions of the device 100 and tissues adjacent the penetrationsite while still providing stabilization to the penetrable region of thedevice 100. For example, the distal extension 117 of the neck can besufficiently long and contoured such that the reservoir 130 of thedevice is located a distance away from the adjacent tissue layers of thepenetration site even when the reservoir 130 is in the expandedconfiguration. In some implementations, the distal extension 117 of theneck has a length and contour configured to prevent any portion of thedevice 100 distal to the extension 117 from contacting any of theinternal structures of the eye except the vitreous 30 within which it isimplanted. In some implementations, upon implantation and expansion ofthe device 100 in the eye, the flange element 110 and the proximalregion 116 of the neck come into contact with the tissue layers of theeye (e.g. conjunctiva, sclera, ciliary body, and/or choroid. Thedistally extending portions of the device 100, such as the reservoir130, the drug release element 120, and distal portions of the extension117, may avoid contact with the tissue layers of the eye and come intocontact only with the vitreous 30. The shape of the reservoir 130 in theexpanded configuration can also aid in preventing this contact as willbe discussed in more detail below.

As mentioned above, the devices described herein can include one or moredrug release elements 120. The drug release element 120 can bepositioned adjacent and/or within the one or more outlets 125 such thatthe drug release element 120 can control or regulate the delivery of theone or more therapeutic agents from the reservoir 130 through the one ormore outlets 125. The contents of the reservoir 130 can be deliveredgradually via diffusion rather than expelled as a fluid stream. In someimplementations, the one or more drug release elements 120 can bedisposed within a region of the reservoir 130, such as a distal endregion, or a region proximal to the distal end region of the device. Insome implementations, the drug release element 120 can be a covering orlining having a particular porosity to the substance to be delivered andcan be used to provide a particular rate of release of the substance.The drug release element 120 can be a release control element, includingbut not limited to a wicking material, permeable silicone, packed bed,small porous structure or a porous frit, multiple porous coatings,nanocoatings, rate-limiting membranes, matrix material, a sinteredporous frit, a permeable membrane, a semi-permeable membrane, acapillary tube or a tortuous channel, nano-structures, nano-channels,sintered nanoparticles and the like. The drug release element 120 canhave a porosity, a cross-sectional area, and a thickness to release theone or more therapeutic agents for an extended time from the reservoir.The porous material of the drug release element 120 can have a porositycorresponding to a fraction of void space formed by channels extendingthrough the material. The void space formed can be between about 3% toabout 70%, between about 5% to about 10%, between about 10% to about25%, or between about 15% to about 20%, or any other fraction of voidspace. The drug release element 120 can be selected from any of therelease control elements described in more detail in U.S. Pat. No.8,277,830, which is incorporated by reference herein.

As mentioned above, the devices described herein include a reservoir 130configured to expand, unfold, or otherwise enlarge from a generallyminimally-invasive insertion configuration to an expanded configurationwith an increased volume. The insertion configuration of the devicesdescribed herein has a three-dimensional shape that is relatively lowprofile such that the device 100 can be inserted at least partially intothe eye using a small gauge device, or directly into the eye through asmall incision. Many of the devices described herein can be insertedusing an incision or puncture that is minimally-invasive, for example ina range of about 1 mm to about 5 mm. In some implementations, theincision is a 3.2 mm incision. It should also be appreciated that insome implementations, the device 100 can have column strength sufficientto permit the device 100 to pierce through eye tissue without aninternal structural support member or members. The device can beinserted through the sclera 24 without a prior incision or puncturehaving been made in the eye. For example, the device can be insertedusing a needle cannula member extending through an interior of thedevice and the drug release element 120 pressed or secured inside at adistal tip of the cannula member.

Generally, when in the insertion configuration the portion of the device100 configured to penetrate the eye (e.g. the reservoir 130) can have asmaller cross-sectional diameter compared to the cross-sectionaldiameter of the portion of the device 100 configured to remain externalto the eye (e.g. the flange element 110). In some implementations, thecross-sectional diameter of the reservoir 130 (e.g. collapsed around acentral core element 135 as will be described in more detail below) inthe insertion configuration can be about 1.3 mm to about 1.5 mm indiameter, the diameter of the proximal portion 116 of the neck can beabout 2.7 mm long and about 1.5 mm wide, and the flange element 110 canbe about 4.5 mm long and about 3.8 mm wide. In some implementations, thedevice 100 can be approximately 25 gauge such that the device 100 can beinserted through a needle bore. In this implementation, the flangeelement 110 can be of a resilient material (such as shape memory or aflexible silicone) such that it can be housed in the needle bore duringimplantation and released out the distal end of the needle bore at whichpoint the flange element 110 can retake its shape. Further, thecross-sectional shape of the eye-penetrating portion of the device 100when in the insertion configuration can vary including circular, oval,or other cross-sectional shape. Also, when in the insertionconfiguration the device 100 can have a substantially uniform diameteralong its entire length or the cross-sectional dimension and shape canchange along the length of the device 100. In some implementations, theshape of the device 100 in the insertion configuration can be selectedto facilitate easy insertion into the eye. For example, the device 100can be tapered from the proximal end region to the distal end region.

The length of the device 100 can vary depending on where and how thedevice 100 is to be implanted in the eye. Generally, the length isselected so as not to impact or enter the central visual field or crossthe visual axis 27 of the eye upon implantation and filling of thedevice 100. In some implementations, the total length of the device canbe between about 2 mm to about 10 mm. In some implementations, the totallength of the device can be between about 3 mm to about 7 mm. In someimplementations, the length of the intraocular region of the device isabout 4 mm to about 5 mm long.

The reservoir 130 of the devices described herein can enlarge into aparticular contour or shape that can maximize its overall capacity whileminimizing its impact on the internal eye anatomy. The insertionconfiguration of the reservoir 130 can have a first three-dimensionalshape and the expanded configuration can have a second three-dimensionalshape that is different from the first. Again with respect to FIGS. 2and 3 , the reservoir 130 in the expanded configuration can be generallysymmetrical relative to the insertion axis A. In this implementation,both the first three-dimensional shape and the second three-dimensionalshape can be generally concentric with the longitudinal axis of thedevice 100 and the insertion axis A. In another implementation as shownin FIGS. 4-9 , the reservoir can be configured to enlarge from aninsertion configuration having a first three-dimensional shape to anexpanded configuration having a second three-dimensional shape, whereinthe second three-dimensional shape is eccentrically positioned orgenerally asymmetrical relative to the insertion axis A. In thisimplementation, the first three-dimensional shape can be generallyconcentric with the insertion axis A and the second three-dimensionalshape can be eccentric with the insertion axis A. Depending on thefolding approach used to obtain the low profile insertion configurationof the reservoir, the first three-dimensional shape of the symmetricalor eccentric reservoirs may be offset as opposed to generallyconcentric. The first three-dimensional shape of the generallysymmetrical reservoir 130 may be slightly offset from the longitudinalaxis of the device and the insertion axis A such that even though thereservoir expands into a generally symmetrical second three-dimensionalshape, the first three-dimensional shape is somewhat non-concentric. Thesame can be true for the eccentrically positioned reservoir 130. Thefirst three-dimensional shape may depend on the overall shape of thereservoir 130 as well as on the folding approach used to obtain the lowprofile insertion configuration and can be somewhat non-concentric.

FIG. 9 shows a top down view of a device 100 and illustrates an axis ofinsertion A. A plane can be drawn parallel to the axis of insertion Aand orthogonal to the surface of the sclera 24 through which the deviceis inserted. In some implementations, more of the expanded volume of thereservoir 130 can be located on a first side of this plane than on theopposite side of this plane such that the expanded volume on the firstside extends towards a posterior region of the eye or enlarges away fromthe lens 22 of the eye such that contact with the lens 22 is mitigated(see, e.g. FIG. 5 and also FIG. 13 ). Thus, a portion of the overallvolume of the reservoir 130 in the expanded configuration enlarged awayfrom the lens of the eye and is greater than the remaining portion ofthe reservoir 130 volume. Further, the reservoir 130 can enlarge suchthat a majority of the reservoir volume extends away from the innersurface of the sclera through which the device was inserted such thatthe expanded reservoir 130 avoids contacting interior surfaces of theeye that can contribute to choroidal effusions, hemorrhage or causeother unintentional contact, damage or irritation between the eye andthe device 100, such as with the ciliary body or choroid. Further, whenin the expanded configuration the entire reservoir 130 can remaingenerally outside the central visual field, such as outside the visualaxis of the eye.

The expandability of the reservoir 130 from a low profile dimension forinsertion to an expanded profile dimension after insertion allows forthe device to be inserted in a minimally-invasive manner and also havean increased reservoir capacity. This increased reservoir capacity, inturn, increases the duration of drug delivery from the device for agiven release control element such that the device 100 need not berefilled as frequently, and/or can reach the targeted therapeuticconcentration of drug in the eye. In some implementations, the volume ofthe reservoir 130 can be between about 0.5 μL to about 100 μL. In someimplementations, the volume of the reservoir 130 can be at least about 1μL, 2 μL, 3 μL, 4 μL, 5 μL, 10 μL, 15 μL, 20 μL, 25 μL, 30 μL, 35 μL, 40μL, 45 μL, 50 μL, 55 μL, 60 μL, 65 μL, 70 μL, 75 μL, 80 μL, 85 μL, 90μL, 95 μL, 96 μL, 97 μL, 98 μL, 99 μL, 100 μL, 105 μL, 110 μL, 115 μL,120 μL, 125 μL, or other volume.

An outer wall of the reservoir 130 can be formed of a substantiallynon-compliant material that is expandable yet rigid and/ornon-distensible material. As such, the reservoir 130 can be filled intothe expanded configuration, but the material of the reservoir 130 isconfigured to maintain its shape and does not stretch so as to avoid anunintentional driving force created by the memory of the wall materialof the reservoir 130. In other implementations, the outer wall of thereservoir 130 can be a compliant material such that a controllablepressure can be provided by the compliant wall of the reservoir 130 upto the point of pressure equalization, for example, to provide a smallinitial boost of drug delivery from the reservoir after filling.Examples of expandable, non-distensible, substantially non-compliantmaterials are provided herein, including but not limited to PET, Nylon,and acrylics. Examples of expandable, compliant materials are alsoprovided herein, including but not limited to silicone, urethane, andacrylics.

In some implementations, the volume of the reservoir 130 and the shapeof the reservoir 130 in the expanded configuration are selected tomaximize the payload capacity as well as maximizing the distance awayfrom the lens 22 and/or the sclera 24 adjacent the penetration site. Forexample, in some implementations, the volume of the reservoir 130 can be60 μL and the shape of the reservoir 130 in the expanded configurationcan be D-shaped, C-shaped, elliptical, eccentric, or other shape thatcan extend away from the insertion axis A of the device (see FIG. 6 ).Thus, compared to a symmetrically expanded reservoir of smallercapacity, the eccentric or asymmetrically expanded reservoir 130 canmaintain a greater distance D away from the lens 22. The reservoir 130in the expanded configuration also can be tapered on a proximal end tomaximize the distance D′ the expanded reservoir 130 is off-set from thesclera 24 through which the device extends. Maintaining a greaterdistance D′ helps to prevent contact between the expanded reservoir 130,for example the proximal end of the expanded reservoir 130, and theinternal tissue surfaces surrounding the penetration site and otherneighboring tissue layers of the eye such as the retina 26, choroid 28,sclera 24, ciliary body 20, and/or the lens 22. The proximal tapering ofthe reservoir 130 also allows for improved removal of the device 100from the eye. The shape of the reservoir 130 can alternatively oradditional be tapered on a distal end. A distal end taper can furtherhelp the device to avoid entering the visual axis and avoid contact withcertain internal structures such as the lens. Further, a smooth andgradual transition to the end of the device can also improve the ease ofinsertion as will be described in more detail below.

As best shown in FIGS. 7 and 8 , the devices described herein caninclude a central core element 135 extending between the proximal endregion of the device 100 and the distal end region of the device 100.The central core element 135 can be a generally cylindrical andrelatively rigid element positioned around a longitudinal axis of thedevice 100 such that it is generally concentric with the axis ofinsertion A. The central core element 135 can include an inner lumen 137and one or more openings 139 extending through a wall of the centralcore element 135. In some implementations, the central core element 135can include an inlet 138 on a proximal end positioned relative to thepenetrable element 115 in the access portion to receive materialinjected into the device, which will be described in more detail below.The inlet 138 or a portion of the central core element 135 near theinlet 138 can be surrounded by the distal extension 117 of the retentionstructure 105. The central core element 135 can also include an outletlocated a distance away from the inlet 138 that can form the outlet 125from the device 100, for example near a distal end of the central coreelement 135. The drug release element 120 can be positioned within theoutlet such that therapeutic agent can be released from the reservoir130 into the eye. The central core element 135 can protect the materialof the reservoir 130 from unintended penetration or puncture. Forexample, during filling a portion of the central core element 135 nearthe inlet 138 can receive a fill needle configured to inject materialinto the device. The central core element 135 can be formed of amaterial that is relatively rigid and less likely to snag on the sharptip of the fill needle compared to the substantially non-compliant yetthinner material of the reservoir 130. Thus, the rigid core element 135can prevent penetration of reservoir material near the inlet 138 by theneedle during filling. The core element 135 can also aid in surgicalcontrol during insertion and/or removal by providing a degree ofrigidity along the longitudinal axis A of the device.

The one or more openings 139 in the wall of the central core element 135allow for fluid communication between the inner lumen 137 of the centralcore element 135 and the reservoir 130. Material introduced through thepenetrable element 115 such as via a delivery element can be injectedwithin the lumen 137 and the flow of fluid directed through the one ormore openings 139 into the reservoir 130. The introduction of materialinto the reservoir 130 expands the inner volume of the reservoir 130 andcauses the pliable walls of the reservoir 130 to move away from thelongitudinal axis of the device and/or move away from the central coreelement 135. Expansion of the reservoir volume changes the reservoirfrom the initial, insertion configuration to the expanded configuration,which will be described in more detail below. Optimizing the size of theone or more openings 139 in relation to the diameter of the inner lumen137 can help to direct flow through the central core element 135 throughthe one or more openings 139 into the reservoir 130. The size and numberof the one or more openings 139 can vary. In some implementations, theopening(s) 139 through the wall of the central core element 135 aresmaller in diameter than an outer diameter of the insertion tool 1400and/or an outer diameter of the needle 270 of the exchange needleapparatus 200. This prevents the insertion tool 1400 or needle 270 frominadvertently inserting through the opening(s) 139. The smaller sizeopenings 139 can protect against punctures or other damage to theflexible reservoir 130 from the insertion tool 1400 and/or the tip 212of the needle 270 (FIG. 16 ). The smaller size of the one or moreopenings 139 can be compensated for by increasing the number of openings139 present. In some implementations, the central core element 135 canhave at least about 2 openings 139, at least about 10 openings 139, atleast about 20, 30, 40, 50, up to about 100 openings 139 extendingthrough the wall of the central core element 135. In someimplementations, at least about 1000 openings 139 can extend through thewall of the central core element 135. The openings 139 can be less than150 um openings. In some implementations, the openings 139 can be about10 um up to about 150 um. The smaller and more numerous openings 139prevent the tip 212 of the needle 270 or the insertion tool 1400 fromprotruding through opening(s) 139 in the wall of the central core 135during use. The opening(s) 139 can be any geometric shape (orcombinations of shapes) and distributed in any arrangement or pattern inthe wall of the central core 135. A few specific configurations areshown in FIGS. 7, 8, 10 , and 11 for exemplary purposes only. Many otherconfigurations are possible as understood by those of skill in the art.

The central core element 135 can also include a flow director 140 tofacilitate filling/refilling of the reservoir 130 and increaseefficiency of filling/refilling (see FIG. 10 ).

In some implementations, the flow director 140 can include a firstcylindrical region 142 coupled to a second cylindrical region 144 by afunnel shaped region 146 to direct flow through the one or more openings139. The first cylindrical region 142 can be positioned proximal to thesecond cylindrical region 144 the second cylindrical region 144. Thefirst cylindrical region 142 can have a larger cross-sectional diameterthan the second cylindrical region 144. Further, the one or moreopenings 139 of the flow director 140 can be smaller in size than in animplementation of the device without a flow director 140. In anotherimplementation, the flow director 140 positioned within the inner lumen137 of the central core element 135 can be a penetrable barrier, forexample an element through which a delivery element extends (see FIG. 11). In this implementation, the flow director 140 can be a siliconeelement that has an outer diameter sized and shaped to wedge within theinner lumen 137 of the core element 135. For example, the flow director140 that is a penetrable element can be penetrated by a fill/refillneedle or other delivery element such that the device 100 can befilled/refilled from the bottom up. The material can be initiallyinjected in a distal end region of the device until the proximal endregion of the device is also filled and expanded. The fill/refill needleis described in more detail below.

The devices described herein having a flow director 140 or other corestructure with optimized openings 139 can leverage paths of leastresistance for evacuation of pre-existing materials from the devicebeing filled. This, in turn, can improve refill efficiency at lowerrefill volumes for example, by preventing backflow and/or directingbottom-up or bottom-first filling. Bottom-up filling can be improved,even without the presence of a flow director, by leveraging fluiddensity differences of the liquids being exchanged. The fluid density ofthe new solution being added to a device can be greater than the fluiddensity of the pre-existing material in a device. Temperaturedifferences between the liquids being exchanged impact fluid density aswell and can be leveraged to improve exchange efficiency in bottom-upfilling. For example, the temperature of the pre-existing material inthe device is at body temperature whereas the temperature of the newsolution can be at room temperature or colder temperatures such that itis denser compared to the warmer material in the device. These densitydifferences allow for bottom-up filling/exchange to occur in a moreefficient manner with less mixing. Additionally or alternatively, highvolume exchange can be used to flush and/or refill the device with a newsolution.

In some implementations, implant orientation and/or tilt angle duringrefilling can improve the refill efficiency of the reservoir,particularly where there is a solution density difference between thefluid being injected and the contents of the implant remaining in thereservoir prior to refill. The patient can be positioned during a refillprocedure to maintain the implant reservoir (or a majority of thereservoir) below the level of the proximal openings in the implant core(i.e. the openings nearest the septum). The refill of the implant can beperformed similarly as an intravitreal injection. The needle pathpenetration techniques used is generally along the longitudinal axis ofthe implant to avoid snagging the needle tip on the inner core. Theimplant can be positioned through the sclera with the elongatecross-sectional profile aligned with an incision along the pars plana soas to extend from the pars plana region into the vitreous. Refill of theimplant can be performed by inserting the refill needle along thelongitudinal axis of the device. The patient having an implant extendingthrough the sclera of an eye such that the reservoir positioned withinthe vitreous can be oriented relative to gravity to maintain a majorityof the reservoir below the level of the proximal openings in the core toachieve the greatest refill efficiency.

In some implementations, controlled aspiration of the reservoir 130 canbe used to improve refill efficiency. Aspiration can improve refillefficiency without relying on fluid density differences, high volumeexchange, and/or a flow director. For example, aspiration can be appliedto remove material from the reservoir chamber prior to filling thedevice with new solution. The new solution can be injected into thereservoir chamber emptied by aspiration, such as by applying positivepressure through an injection lumen. Optionally or additionally, the newsolution can be drawn into the reservoir chamber as a result of theaspiration used to evacuate the pre-existing material from the reservoirchamber. This evacuation and refilling can be a two-step process (i.e.aspiration step to evacuate followed by an injection step to fill) orcan be performed in an essentially one-step process (i.e. aspirationstep to evacuate leading to filling by drawing fluid into thereservoir). For example, a vacuum can be applied through a first channelin the exchange apparatus such that new solution is drawn in from areservoir through a second channel of the exchange apparatus. Theconfiguration of such an exchange apparatus can vary.

The configuration of the flow director 140 can vary. The central core135 can include one or more directional fins or projections internal tothe central core 135. The projections in the central core 135 can changedirection of flow out the openings in the central core 135. For example,the projections can slope towards the openings to direct flow towardsthe distal edges of the walls of the reservoir 130. The projections canoptimize flow patterns of injected therapeutic agent and encourageadditional mixing in possible low-flow regions of the device. Inbottom-up type exchange as described above, it is desirable to minimizemixing between the pre-existing material in the device with the newsolution being added. However, in some instances some degree of mixingbetween the pre-existing material and the new solution may be desirable.The device may have regions where displacement during exchange isdifficult due to geometry of the interior of the device (e.g. corners,edges) and some mixing with the flow director 140 may be helpful duringthe exchange.

As mentioned above, the treatment devices described herein can be heldby an insertion tool and inserted through the puncture or incision intothe target region. As such, the distal end region of the devices can beshaped in order to ease initial wound entry. A distal end region of thedevice having a larger diameter and/or a flatter distal tip can be moredifficult to find and insert through an incision or puncture as small as3.2 mm. Further, abrupt edges in the outer contour of the device due tobonding between structural elements of the device (e.g. where a distaledge of the reservoir material bonds to the central core element) cannegatively impact tissue entry. In some implementations, the distal endregion of the treatment device is beveled, tapered or has a bullet-pointtip or other element such that it smoothly penetrates the tissue duringimplantation.

As mentioned above, the central core element 135 can be bonded at aproximal end to an upper portion of the reservoir 130 and at a distalend to a lower portion of the reservoir 130. The bond between thecentral core element 135 and the reservoir 130 as well as the centralcore element 135 and the drug release element 120 can be achieved byadhesives such as a two-part epoxy like Epotech 301. In someimplementations, thermal fusing between the components is used. Forexample, if the central core element 135 and the reservoir material canboth be made from thermally bondable materials, such as nylon orpolysulfone (PSU), the two may be thermally bonded together using heatand compression providing a simpler manufacturing process and morereliable bond than adhesive. The central core element 135 also can beformed of a metal material and designed to accept the flow of plasticsuch that it can be joined to the reservoir using heat and compressiondespite not be formed of the same thermally bondable material. In someimplementations, the distal and/or proximal region of the central coreelement 135 can incorporate a plurality of small holes to accept theflow of a polymer material such as a small hole pattern laser drilledinto the core. If the reservoir material and the central core elementare made from similar materials or the core has features designed toaccept the flow of a polymer material an ultrasonic welding process canbe used to provide energy required to create the bond between them. Infurther implementations, the central core element 135 can be formed of athermoplastic that can allow for the development of an over-moldingprocess between the drug release element 120 to create a bond jointbetween the drug release element 120 and the central core element 135 atthe distal end of the device.

It should be appreciated that the devices described herein need notinclude a flow director 140 or a central core element 135. For example,FIG. 12 shows an implementation of a device 100 having an expandablereservoir 130 coupled on a proximal end to a retention structure 105having a flange element 110, a penetrable barrier 115 positioned withinan access port 111 and a distal extension 117. The expandable reservoir130 is coupled on a distal end region to an outlet 125 having a drugrelease element 120 positioned therein. However, there is no centralcore element 135 or flow director 140 incorporated. The material of thereservoir 130 can provide sufficient rigidity to the device such that itcan be inserted through a penetration site along an axis of insertion Awithout collapsing in on itself or warping away from the insertionconfiguration or axis of insertion A. In some implementations, thematerial of the reservoir 130 is Polyethylene terephthalate (PET) andhas a wall thickness in the range of about 0.0005 mm to about 0.05 mmsuch that the device has column strength and is generally rigid enoughto insert into the eye without a central core element or flow director.In some implementations, the devices described herein can be implantedusing a stylet or other rigid, longitudinal element that can be insertedwithin a region of the reservoir at the time of placement and thenremoved once the necessary column strength has been imparted and thedevice has penetrated through the sclera. The material of the reservoir130 can also include Urethane, Nylon, Pebax®, Polyurethanes,cross-linked polyethylene, FEP, PTFE, and similar materials and blendsof materials. The materials may also include multiple layers of theabove materials and other materials known in the art for manufacturingexpandable elements.

As discussed above, the device can include a proximal retentionstructure 105 having a smooth protrusion or flange element 110configured to remain generally external to the eye to aid in retentionof the device 100 when the remainder of the device 100 is implantedintraocularly. In some implementations, the flange element 110 can bedesigned to provide an identifiable orientation of the device 100 forimplanting in the eye such that the direction of expansion of aneccentrically expanding reservoir 130 is predictable and according to adesired orientation. The reservoir 130 once implanted within thevitreous 30 may not be directly visualized. Thus, an orientationindicator 150 on a portion of the device 100, such as the flange element110, that can be visualized from outside the eye allows a user to knowthe expansion of the reservoir 130 will be in the correct plane. Forexample, FIG. 9 illustrates an orientation indicator 150 that is a dotor other visual indicator on an upper surface of the flange element 110.FIG. 13 illustrates an orientation indicator 150 that is a shape of theflange element 110 that indicates the orientation of the eccentricvolume of the reservoir. For example, because the expandable reservoirs130 can be designed to enlarge along a particular orientation relativeto the longitudinal axis of the device and/or the insertion axis A, therelative orientation of that portion of the expandable reservoir 130around the axis A can be critical in ensuring the device does notimpinge on certain intraocular structures. In some implementations, theflange element 110 can incorporate a mark or other orientation indicator150 on an upper surface 112 that is visible to a user to indicateorientation of reservoir filling. The orientation indicator 150 can beany of a variety of shapes, colors or combination of shapes and colorsproviding guidance regarding where the eccentric volume is located.Alternatively or additionally, the orientation indicator 150 can be theshape of the flange element 110 itself. For example, the flange element110 can be shaped in such a way to provide directional guidance to auser for implantation of the device. The flange element 110 can have avariety of shapes such as an ovoid, elliptical, polygonal, triangular,or diamond shape or other shape such as an arrow having a side or angleor portion that indicates where the reservoir 130 is designed to have agreater expansion compared to another side of the reservoir 130. FIG. 13illustrates a flange element 110 having a particular shape indicatingorientation of the eccentric region of the reservoir 130. Upon filling,the orientation indicator 150 will indicate to a user the portion of thereservoir 130 that will enlarge away from one or more internalstructures of the eye, such as the lens 22. It should be appreciatedthat the flange element 110 can be keyed or configured to couple with afill device having keyed features that also provides visual feedback tothe user regarding the orientation of the eccentric volume of the deviceprior to fill or refilling.

The penetrable element 115 may additionally or alternatively include acolor or other indicator to improve guidance during injections. At leasta portion of the material of the penetrable element 115 can be coloredor a colored element added to an outer surface of the penetrable element115. The color selected can vary, including, but not limited to black,white, red, blue, orange, yellow, green, purple, or other variants inbetween. The material of the penetrable element 115 can also betranslucent such that it appears dark from above due to the reservoirchamber underneath it. The color of the material of the penetrableelement 115 can also be made into a pattern, such as stripes or hatchedappearance, or a shape, such as a circle or target. Generally, the colorof the material of the penetrable element 115 is selected to provideheightened contrast relative to the remainder of the device as well asthe tissues surrounding the device upon implantation.

The devices described herein can incorporate expanding reservoirs thatare also symmetrically distributed in the expanded configuration. Aspreviously shown in FIGS. 2 and 3 , the reservoir 130 can enlarge fromthe insertion configuration to an expanded configuration such that thevolume of the reservoir 130 is symmetrically distributed about thelongitudinal axis of the device as well as the axis of insertion A. Inanother implementation, the devices described herein can have expandedconfigurations that are symmetrically distributed, but the overall shapeof the device itself can be formed into a curvilinear or other shapethat is not aligned with the axis of insertion A.

The treatment devices described herein can be designed for prolongedretention in the eye to deliver drug to the vitreous for an extendedperiod of time. The way in which the treatment devices described hereinare retained in the eye can vary. For example, in some implementationsthe treatment device can include a proximal retention structure having aflange element that is configured to reside extra-sclerally and work inconcert with portions of the device residing trans- or sub-sclerally toaffix the device to the eye and provide stability during use. Otherimplementations of the treatment devices described herein have noextra-scleral retention structure per se and rely upon suturing to thesclera to affix the device to the eye. For example, the device can beimplanted trans- and/or sub-sclerally and a proximal region of thedevice sutured to the sclera to affix the device to the eye. In furtherimplementations, the treatment devices described herein may have anextra-scleral retention structure providing fixation that is furtherenhanced by suturing. For example, the flange element of the retentionstructure can incorporate one or more anchor features to enhancefixation or stabilization of the device in the eye, including, but notlimited to holes, indentations, or other features that provide alocation for suturing of the device to the eye. Some additionalretention and stabilization features for use with the treatment deviceswill be described in more detail below.

As described elsewhere herein the proximal aspects of the implants(sometimes referred to herein as the “upper region” or “trans-scleralregion” or “neck”) allow for re-charging of the implant depot/reservoirfrom outside the eye. For example, the arrangement of the retentionstructure, if present, relative to the eye tissue ensures the penetrableelement is accessible from outside the eye such that techniques commonlyemployed for direct intravitreal injections of the eye can be used torefill and/or flush the reservoir of the implant. As will be describedin more detail below, placement of the implants described herein caninvolve the temporary resection of the conjunctiva followed by creationof an incision of fixed length (e.g. 3.22 mm) in the pars plana regionusing a flat surgical blade. Implants such as those described herein canallow for persistent physical access such as via a needle-type accessoryand can physically contact trans-scleral tissues including one or moreof the sclera, scleral blood vessels, the choroid, and possibly adjacentretinal and/or ciliary body tissues. The insertion of the implant in thetrans-scleral region can cause a physical interference between theimplant and the tissues of the eye adjacent the implantation site thatcan disrupt the edges of the incision and prevent the tissues fromreturning to a more natural or relaxed state around the implant.Further, the choroid can be disturbed upon penetration of thetrans-scleral and sub-scleral components of the implant at the time ofsurgical implantation, which can increase risk of acute delamination ofthe tissue layers and contribute to the risk of bleeding at the site ofimplantation at the time of surgery that can lead to vitreoushemorrhage. The devices described herein can incorporate features thatalthough they may pass through the scleral interface with the choroidfor proper implantation in the eye, the risk of delamination andvitreous hemorrhage is minimized while still providing sufficientfixation in the eye, and a resealing septum region to provide effectivesealing following multiple needle penetrations over time for prolongedtreatment with the device.

In some implementations, the major diameter of the trans-scleral regionof the device (as well as any portion of the device passing through thesclera) is no greater than the length of the incision, and preferablysmaller than the length of the incision, which can be between about 1 mmto about 5 mm. The dimensions of the treatment devices described hereingenerally avoid stretching of the incision during implantation andsubsequent use. In some implementations, the minor diameter of theretention structure 105, which is primarily responsible for ‘propping’open the tissue edges of the incision, can be minimized. Minimization ofthe trans-scleral regions of the device allows for the device to beinserted in a manner that does not enlarge the incision and allows forthe tissue edges to be in a more relaxes state around the implant neckor upper end region and minimize disturbance to ocular wall tissuestructures (e.g. choroid). In some implementations, the largest minordiameter of the trans-scleral region of the implant can be no greaterthan and preferably less than 3.3 mm, 3.2 mm, 3.1 mm, 3.0 mm, 2.9 mm,2.8 mm, 2.7 mm, 2.6 mm, or 2.5 mm. In some implementations, the largestminor diameter of the trans-scleral region is between about 1.0 mm toabout 2.6 mm.

The penetrable barrier of any of the treatment devices described hereincan include those described in U.S. Publication No. 2014/0296800, andU.S. Provisional Application Ser. No. 62/318,582, filed Apr. 5, 2016,which are incorporated by reference herein. The penetrable barrier canincorporate one or more features providing enhanced retention of thepenetrable barrier within the access port using any of a number offeatures as described therein. For example, the penetrable barrier canbe shaped to mate with a corresponding region within the access port.The penetrable barrier can incorporate one or more features such as askirt region configured to extend past the access port into thereservoir volume to further support retention. The device can include acover to improve the integrity of the penetrable barrier and its sealingengagement with the access port. The access port can include an inneranchor feature such as a donut-shaped element configured to encircle atleast a region of the penetrable barrier and/or a secondary penetrablebarrier positioned above and/or below the primary penetrable barrier.The penetrable barriers described herein need not be a septum formed ofa penetrable material. For example, any of the treatment devicesdescribed herein can incorporate a valve mechanism with or without aseptum as the penetrable barrier. The valve can be configured to receivean elongate fill device through it, such as a blunt needle or elongatecannula, for filling of the reservoir with a drug. The valve can beconfigured to open upon application of a force in the distal directionby the fill device. The opening of the valve can permit the fill deviceto form a fluid tight engagement and allow fluid communication between afluid container attached to the fill device and the reservoir of thetreatment device. The valve and the fill device can be configured toseal during injection such that fluid enters the reservoir in a mannerthat prevents fluid from leaking between the valve/fill deviceinterface. The configuration of the valve can vary, including, but notlimited to a split septum, a check valve, a ball valve, a flap valve, adisc valve, a duckbill valve, or other valve configuration. In someimplementations, the penetrable barrier can be a twist valve. The twistvalve can include a tortuous path that prevents fluid from entering orexiting the device. The fill needle can include a sharp element forpenetration of an outer septum material and a blunt obturator forinsertion through the tortuous path. As the obturator is insertedthrough the tortuous path it straights the path until a distal tip ofthe fill needle is located within the reservoir such that material canbe inserted/withdrawn from the reservoir. Upon removal of the fillneedle from the path, the tortuosity of the path returns maintaining thefluid-tight seal.

Any of the device implementations described herein can incorporate oneor more features that provide for fixation of the device in the eye inany combination. The features can include the proximal retentionstructure having a flange element configured to be positioned in asupra-scleral location when the treatment device is in use. The featurescan also include the relative shape of the upper end of the treatmentdevice (i.e. proximal region and distal extension) to improvetrans-scleral and/or sub-scleral fixation. The features can also includefeatures that allow for suturing of the treatment device. These featurescan be used alone or in combination. For example, the treatment devicesdescribed herein can rely only upon suturing in place or suturing can beincorporated as an enhanced fixation feature. The treatment devicesdescribed herein need not rely upon suturing for fixation and can relyupon one or more features of the upper end of the treatment device tomaintain the device in place. Thus, the features for fixation of thetreatment device can be sub-scleral, intra-scleral, and or supra-scleralfeatures.

It should be appreciated that the treatment devices described herein canbe used in a variety of locations and implanted in a variety of ways.The implantation method and use of the treatment devices describedherein can vary depending on the type of treatment device beingimplanted and the intended location and drug for treatment. As will bedescribed in more detail below, the treatment devices described hereincan be primed, implanted, filled, refilled, aspirated, and/or explantedusing one or more devices. Where the treatment device is described asbeing primed prior to filling with therapeutic solution, the device mayalso be implanted without priming. For example, the device may beimplanted “dry” and the air expelled from the device as the device isfilled with therapeutic solution or passively dissolved afterimplantation. Similarly, where the treatment devices are describedherein as being removed from the eye, they may also be left implantedindefinitely without delivering therapeutic material.

In one implementation of treatment device implantation, a sclerotomy iscreated according to conventional techniques. The sclerotomy can becreated posterior to an insertion site of the treatment device throughthe sclera 24 or the sclerotomy can be created directly above theinsertion site of the post through the sclera 24. The conjunctiva 16 canbe dissected and retracted so as to expose an area of the sclera 24. Anincision in the conjunctiva 16 can be made remote from the intendedinsertion site of the treatment device. A scleral incision or puncturecan be formed. The scleral incision or puncture can be made with adelivery device tool or using a distal tip of the treatment device, asdescribed above. In some implementations, the treatment device isimplanted using sutureless surgical methods and devices. In otherimplementations, the treatment device can be positioned sub-sclerallysuch as under a scleral flap. The post can be inserted into the eye(such as within the vitreous or the anterior chamber, etc.) until atleast one of the outlets is positioned within or near the targetdelivery site and, if a flange element is present, until theinner-facing surface of the flange element can abut an outer surface ofthe eye. An additional fixation element can be used such as a suture orother element if needed following implantation of the treatment devicein the eye as described elsewhere herein. The treatment device canremain in position to deliver the one or more therapeutic agents to theeye for a period of time including, but not limited to 1, 2, 3, 4, 5,10, 15, 20, 25 days or any number of days, months and year, up to atleast about 3 years. After the therapeutic agent has been delivered forthe desired period of time, the treatment device can be refilled forfurther delivery or removed.

Generally, the implementations of the treatment devices described hereincontain drug solutions, drug suspensions and/or drug matrices. Thetreatment devices described herein can also contain therapeutic agentsformulated as one or more solid drug core or pellets formulated todeliver the one or more therapeutic agents at therapeutically effectiveamounts for an extended period of time. The period of time over whichthe treatment device delivers therapeutically effective amounts canvary. In some implementations, the treatment device is implanted toprovide a therapy over the effective life of the device such that refillof the device is not necessary.

FIGS. 14A-14D show a generalized tool 1400 designed to prime, filland/or refill the treatment devices described herein. The tool 1400 caninclude a trocar introducer cannula or outer sheath 280 having aninternal lumen through which an internal fill cannula or needle 270 canextend. The sheath 280 can extend through the penetrable element 115 inthe proximal region of the device 100 until the distal end of the sheath280 enters a proximal end region of the reservoir 130 (see FIG. 14B)and/or the proximal end of the central core element 135, if present. Aregion of the tool 1400 can have a stop (not shown) to prevent thedistal tip 212 from extending too far into the reservoir 130. The needle270 can extend through the internal lumen of the sheath 280 and into atleast the proximal end region of the reservoir 130 (see FIG. 14C). Theneedle 270 can extend further into the reservoir 130 towards a distalend region of the reservoir 130. The overall length of the needle 270can be selected based on the treatment device with which it will be usedsuch that the needle 270 can extend towards a distal end region of thereservoir 130 or the central core element 135, if present. Or if thedevice includes a flow director 140, the needle 270 can have a lengthconfigured to extend through at least a region of the flow director 140.The needle 270 can include a distal tip 212 having an opening 214through which material may flow out of the needle 270 (see FIG. 14D).The distal tip 212 can be sharp or can be blunted. The flow of materialthrough the needle 270 and out the opening 214 near the distal tip 212allows for filling of the reservoir 130 in a bottom-up manner. A distalend region of the sheath 280 can be configured to receive pre-existingmaterial from the reservoir 130 such that it can be flushed out from thereservoir 130 upon filling with new material through the needle 270.This in combination with a flow director 140 can increase refillefficiency.

The tool 1400 can incorporate one or more features of other refilldevices described, for example, in U.S. Pat. Nos. 8,399,006; 8,623,395;U.S. Publication No. 2013/0324918; and U.S. Publication No.2013/0165860, which are each incorporated in their entireties herein. Itshould be understood that depending on the overall length of the accessregion as well as the penetrable barrier installed in the access regionof the treatment device, the fill cannula or needle 270 may have any ofa variety of lengths and/or reinforcement structures. It should also beappreciated that where the needle and sheath are described as beingmovable with respect to one another that they can also be in a fixedconfiguration. As described elsewhere herein, the exchange of fluids canincorporate aspiration as well as positive displacement exchange.

The reservoir 130 can be filled and expanded following implantation andseating of the device. However, it should be appreciated that thereservoir 130 can be filled during or after final seating the treatmentdevice 100 fully within the incision as will be described in more detailbelow. In some implementations, the fill needle can be a 30 gauge needlethat has a hub providing visual feedback via its fluid return path whenthe treatment device 100 has been filled. For example, the fill needlecan include a transparent or translucent chamber for viewing returnfluid. The fill needle can also include one or more return fluid pathholes. The fill needle can be used to inject therapeutic fluid into thedevice 100 until the prime fluid is removed from the treatment device100. The reservoir 130 expands as the device 100 is filled with fluid.The device 100 can be slightly overfilled to ensure maximum expansion.In some implementations, the fill needle can be the same as a primeneedle used to prime and purge air from the treatment device asdescribed above. The fill needle can also be part of an insertion deviceused to hold and deliver the treatment device into position.

FIG. 15 is an implementation of an exchange needle apparatus 200 toexchange fluid of a device 100 to refill the device 100 while it isimplanted in an eye. The apparatus 200 can be coupled to or include asyringe 300 having a container 310 (see FIG. 18C) to inject atherapeutic fluid into the reservoir 130 of the device 100. Theapparatus 200 can include an elongate structure 201 that can be placedsubstantially within at least a portion of the device 100. The elongatestructure 201 can include at least one opening 214 to place thetherapeutic fluid in the reservoir 130 of the device 100 and a pluralityof openings 236 to receive the fluid from the reservoir 130 of theimplantable device 100.

Still with respect to FIG. 15 , the elongate structure 201 can have adistal portion 210, an intermediate portion 220, and a proximal portion230. The distal portion 210 can include a distal tip 212 configured topenetrate the penetrable element 115 of the implantable device 100. Theat least one opening 214 to inject therapeutic fluid into theimplantable device 100 can be found at or near the distal tip 212. Theintermediate portion 220 can include a tapered section 224 to graduallyincrease a size of the channel formed in the penetrable element 115 whenthe elongate structure 201 is advanced through the penetrable element115 so as to maintain integrity of and mitigate damage to the penetrableelement 115. The tapered portion 224 can extend along axis 202 and canbe without holes so as to decrease pressure to the penetrable element115 that may otherwise occur near the edge of a hole. The proximalportion 230 can include the plurality of openings 236 to receive thefluid from the reservoir 130 of the implantable device 100. The elongatestructure 201 can include a stop 240 to limit a depth of insertion ofthe elongate structure 201 into the reservoir 130 of the device 100. Thestop 240 can be a deformable material to engage with the tissue duringinjections. The proximal portion 230 can include an extension 238extending from the stop 240. The extension 238 can be without holes toinhibit leakage when the fluid is exchanged and the stop 240 engages theconjunctiva 16.

When coupled to the therapeutic device 100, the stop 240 can bepositioned to engage the conjunctiva 16 and the elongate structure 201can extend through the conjunctiva 16 and the penetrable element 115into the device 100. The elongate structure 201 can be sized so as toplace the distal tip 212 at a location within the device 100 when thesurface of the stop 240 contacts the conjunctiva 16, for example. Thedistal tip 212 can be located on the elongate structure 201 so as toplace the distal tip 212 at a location from the penetrable element 115within the device 100 that is no more than a desired length, such asabout ¾ of the length of the implantable device 100, and in someimplementations no more than about half of the distance of the device100. The extension 238 can extend substantially through the penetrableelement 115, for example, at least about half-way through the penetrableelement 115 so as to position the plurality of openings away from anexternal surface of the penetrable element 115 and to inhibit leakage.

FIG. 16 shows a detail view of the elongate structure 201 of theapparatus 200 of FIG. 15 . The elongate structure 201 extends along axis202 between the distal tip 212 and the stop 240. The distal portion 210can include an extension 211 having a substantially constantcross-sectional size extending between the tip 212 to penetrate tissueand the intermediate portion 220. As described elsewhere herein, theelongate structure 201 can include an internal fill cannula or needle270 and an outer sheath 280. The needle 270 can extend through aninternal lumen of the sheath 280. The needle 270 can include a distaltip 212 having at least one opening 214 through which material injectedthrough the lumen of the needle 270 may flow out the opening 214. Thedistal tip 212 can be sharp or blunted. The sheath 280 can be configuredto receive preexisting material from the reservoir 130 such that it canbe flushed out from the reservoir 130 upon filling with new materialthrough the needle 270. Thus, the sheath 280 can include at least oneopening into its lumen. The opening can be formed at a distal end of thesheath 280 formed between the outer surface of the needle 270 and theinner surface of the sheath 280. Alternatively, or in additionally, theopening can include a plurality of openings through a wall of the sheath280 as described in more detail below.

Still with respect to FIG. 16 , the extension 211 can include a portionof the needle 270 extending from the stop 240 to the tip 212 of theneedle 270. The tip 212 can be configured to penetrate tissue, such asthe tip of the needle to penetrate conjunctival tissue. The tip 212 andthe opening 214 can be located a distance 204 from the stop 240 and theplurality of openings 236 to provide efficient exchange of the fluidwithin the reservoir 130 of the implanted device 100. In someimplementations, the opening 214 is placed at a distance from the stop240 greater than the plurality of openings 236 such that the opening 214is located distal to the plurality of openings 236. This relativeposition between the opening 214 and the plurality of openings 236 caninhibit mixing of the injected therapeutic fluid moving into thereservoir 130 through opening 214 with the fluid within the implanteddevice 100 moving out of the reservoir 130 through openings 236. Theopening 214 can be separated from the plurality of openings 236 by adistance 208, such that the opening 214 can be located below theplurality of openings 236 when the therapeutic fluid is injected.

The therapeutic fluid may have a density greater than the fluid of theimplanted device and opening 214 can be placed below the plurality ofopenings 236 when the therapeutic fluid is injected to inhibit mixing ofthe fluids (i.e. the fluid moving in from the fluid moving out). Theaxis 100A of the implantable device 100 and the corresponding axis ofthe reservoir 130 can be oriented away from horizontal, such that porousstructure 120 may be located below the penetrable element 115 when thetherapeutic fluid is injected. The axis 202 can be oriented away fromhorizontal such that opening 214 can be placed below the plurality ofopenings 236. The therapeutic fluid having the greater density can flowtoward the distal end of the therapeutic device and the displaced fluidfrom the implantable device having the lesser density can be received bythe plurality of openings 236 located above the opening 214. It shouldbe appreciated that inner needle 270 can be movable relative to theouter sheath 280 or the two components can be in a fixed configurationrelative to one another.

Examples of therapeutic agents and corresponding formulations and fluidsthat may have a density greater than the density of the fluid within thechamber of the implanted device are listed in Table 1 of U.S.application Ser. No. 14/937,784, published as U.S. 2016/0128867, whichis incorporated herein in its entirety. For example, one or more of thetherapeutic agent or a stabilizer can increase the density of thetherapeutic fluid. In many embodiments the therapeutic fluid having thegreater density comprises a stabilizer, such as trehalose, and thetherapeutic agent such as a protein comprising an antibody fragment.Alternatively or in combination, the therapeutic formulation can includean amount of therapeutic agent sufficient to provide a density greaterthan the fluid of the implanted device. The difference in density can bewithin a range from about 1% to about 10% and can depend on the densityof the fluid within the reservoir chamber of the therapeutic device anddensity of the therapeutic fluid placed in the reservoir chamber withthe exchange apparatus. The density of the therapeutic fluid maycorrespond to a density of the therapeutic agent and a density of thestabilizer (when present). In many embodiments, the density of the fluidof the reservoir chamber may correspond to a density of phosphatebuffered saline, or plasma, or an amount of therapeutic fluid remainingin the reservoir from a prior exchange, or combinations thereof, forexample. As described elsewhere herein, differences in fluid density asa result of temperature differences between the exchanged fluids canimprove bottom-up filling efficiency. As mentioned above, implantorientation and/or tilt angle between the implant and the exchangeneedle during refilling can improve refill efficiency where there is asolution density different between the fluid being injected and thecontents of the implant. Aspiration can be incorporated to aid in theefficiency of the exchange as well.

When injected into a device implanted within the patient, the distance204 may correspond to no more than approximately the length of thedevice 140. The distance 204 may be substantially the length of thereservoir 130 (or the central core 135, if present) so as to place thedistal tip 212 near, but not touching the porous structure 120, and theelongate structure 201 of the exchange apparatus 200 can be aligned withan elongate axis 100A of the implantable device 100. In manyembodiments, the distance 204 may correspond to no more than about halfthe distance of the reservoir chamber (or the length of the central core135, if present) such that the elongate structure 201 can be readilyaligned with the implantable device. Work in relation to embodimentssuggests than a distance providing a tolerance for angular alignmenterror of the axis 100A with the axis 202 can facilitate exchange andimprove efficiency of the exchange. The distance 204 from stop 240 totip 212 can be no more than about half of the axial distance of theimplantable device can facilitate alignment during injection.

The intermediate portion 220 can include an extension 222 extendingbetween tapered portion 224 and the distal portion 210. The extension222 can have a cross-sectional size that is smaller than the taperedportion 224. The extension 222 can have a smooth outer surface topenetrate tissue. The tapered portion 224 can have a smother outersurface to penetrate tissue and the penetrable barrier. The outersurface of the tapered portion 224 can extend at an angle of inclinationrelative to the axis, and the tapered portion 224 can include a conicsection having an angle with the axis such that the outer surfaceextends at the angle of inclination relative the axis. The angle ofinclination of the tapered portion 224 can be no more than about 25degrees, for example. The angle of inclination can be about 1 degree,about 2 degrees, about 5 degrees, about 10 degrees, about 15 degrees,about 20 degrees, or about 25 degrees, for example. The extensionportion 216 can have a first cross-sectional dimension, and the portionhaving the plurality of openings 236 can have a second cross sectionaldimension greater than the first dimension, such that tapered portion224 having the angle of inclination extends therebetween to connect theextension portion 216 with the portion having the plurality of openings236.

Still with respect to FIG. 16 , the proximal portion 230 can include theplurality of openings 236 spaced apart along the axis 202 anddistributed circumferentially around the proximal portion to receivefluid from a plurality of circumferential and axial locations when thestop 240 engages the conjunctiva 16 to place the plurality of openingswithin the reservoir chamber. At least one opening 237 of the pluralityof openings 236 can be separated from the stop 240 with a distance 206corresponding substantially to the thickness of the penetrable barrier184, such that the at least one opening 237 of the plurality of openings236 can be placed near the inner surface of the penetrable element 115to receive fluid contacting the inner surface of the penetrable element115. In some implementations, the thickness of the penetrable element115 is within a range from about 0.25 to about 2 mm, for example withina range from about 0.5 to about 1.5 mm, such that the thickness of thepenetrable element 115 is substantially greater than a thickness of theconjunctiva which can be approximately 100 μm. The distance 206corresponding substantially to the thickness of the penetrable element115 can correspond substantially to the thickness of the penetrableelement 115 and the epithelium of the patient.

As mentioned, the outer sheath 280 can be configured to extend over atleast a portion of the needle 270. The sheath 280 can extend along theintermediate portion 220 and the proximal portion 230, and the needle270 can extend through the sheath 280. The sheath 280 can include theplurality of openings 236 and provide one or more channels extendingalong needle 270 to pass the fluid of the implantable device through theseptum.

FIG. 17 illustrates a cross-sectional view of an elongate structure 201of the exchange apparatus 200 having the sheath 280 extending over theneedle 270. The needle 270 can include a channel 219, for example alumen. The channel 219 can be coupled on a proximal end to a syringe 300or other container holding the therapeutic fluid to be injected into thedevice and extend to the distal opening 214 at a distal end region ofthe needle 270. The sheath 280 can include portions corresponding to theintermediate and proximal portions of the elongate structure 201. Theextension 222 can include a distal portion of the sheath 280 having aninner surface sized to engage an outer surface of the needle 270. Insome implementations, the diameter of extension 222 can have an innerdiameter that approaches an outer diameter of the needle 270 to engagethe needle 270 with at least one of pressure or friction. This minimizesdistal-facing space between the needle 270 and the sheath 280 that cancontribute to coring of the penetrable barrier 115 upon insertion of theelongate structure 201 into the device 100. The tapered portion 224 caninclude an intermediate portion of sheath 280, in which the sheath 280has a tapered surface to penetrate the tissue and penetrable element115. The proximal portion 230 can include a proximal portion of thesheath 280 having the plurality of openings 236 and the extension 238.As best shown in FIG. 17 , a channel 239 can extend along an outersurface of the needle 270 to the plurality of openings 236. The channel239 can extend proximally along extension portion 238 toward acollection chamber 250 (see FIG. 18C) to receive the fluid of theimplantable device 100. The channel 239 can couple the plurality ofopenings 236 to the collection chamber 250 to receive the fluid of theimplantable device 100 as will be described in more detail below.

As mentioned, the exchange apparatus 200 can include a syringe 300 orother container 310 configured to hold fluid to be delivered to thereservoir 130. FIGS. 18A-18C show an implementation of an exchangeapparatus 200 having a needle base assembly having a locking connector290 to couple to a syringe 300. The connector 290 can be a lockingconnector having an extension 292 sized to fit in a channel of connector320 of syringe 300, for example. The exchange apparatus 200 can includecomponents of a standard locking needle assembly, for example a standardlocking needle such as a Luer-Lok™ fitting or a pressure fit connector.Alternatively, the connector 290 may include a non-standard connector tolimit access to the exchange apparatus 200. For example, the connector290 can be a star connector or other connector, and connector 290 mayinclude a lock and key mechanism. The lock and key mechanism can have alock on the exchange apparatus 200 configured to receive a key of theinjector, such that the lock of connector 290 can receive the key ofconnector 320 to couple the injector to the exchange apparatus 200 andpermit injection from chamber 310 through opening 214. Alternatively,the syringe 300 may be affixed to exchange apparatus 200, and syringe300 provided with a single dose of therapeutic agent.

The exchange apparatus 200 also includes a collection chamber 250configured to receive fluid from the reservoir 130. The collectionchamber 250 can be defined by a wall 252 configured to surround theneedle 270 extending through the sheath 280. The wall 252 can extend asubstantial distance from the stop 240 and can include at least oneopening 258 that can vent to atmospheric pressure. As will be describedin more detail below, an outlet channel 254 can extend from container250 to the at least one vent opening 258 to atmospheric pressure.

FIG. 18D shows the elongate structure 201 and collection chamber 250 ofthe exchange apparatus 200 of FIGS. 18A-18C. The wall 252 can extendaround a distal portion of collection chamber 250. The needle 270 andsheath 280 can extend through the wall of the collection chamber 250.The stop 240 can be located on a distal portion of wall 252 and can beformed of a soft material, for example, a soft elastomeric material suchas silicone elastomer. The stop 240 can fit within a recess formed onthe surface of wall 252, and the needle 270 and the sheath 280 canextend through the soft elastomer stop 240, for example. The sheath 280can include the tapered portion 224 proximal to the plurality ofopenings 236. The needle 270 can extend from tip 212 through collectionchamber 250 to the connector 290 (see FIGS. 18A-18D), for example. Thesheath 280 can extend from a first end distal of the tapered portion 224to a second end. The second end can include an opening 285 intocollection chamber 250. The outflow path of the displaced fluid from theimplantable device may extend through the plurality of openings 236 tochannel 239, along channel 239 to opening 285, and through opening 285and into collection chamber 250.

FIG. 18E shows various sheath configurations suitable for combinationwith the exchange apparatus of FIGS. 18A-18D. The sheath 280 can beconfigured in many ways (see 280A through 280K), and can have a wallthickness from about 0.0001 inches to about 0.01 inches, for exampleabout 0.001 inches ( 1/1000 inch, 25 μm). The sheath 280 can include aninside diameter sized larger than the outside diameter of needle 270 soas to provide an annular channel 239 extending axially between theneedle 270 and the sheath 280 from the plurality of openings 236 to theopening 285. The diameter of each of the openings 236 can be within arange from about 0.0001 inches to about 0.1 inches, for example within arange from about 0.001 inches to about 0.01 inches. The diameter of eachof the plurality of openings 236 can be uniform or can vary in size aswell as shape. The plurality of openings 236 can be one or more of manyshapes and can be arranged in many ways. Each row can include from about1 to about 20 holes, for example, and can be circular, oval, ellipticalor other shapes, for example. The sheath 280 can include a sheath 280Ahaving four rows of circular holes. Each of the holes can have adiameter of no more than about one half of the thickness of the outsidediameter of the sheath 280, for example, and may be locatedcircumferentially at 90 degrees to each other, for example. Each of thefour rows may extend axially along the sheath 280. The rows can bespaced angularly at 90 degrees to each other, for example. The sheath280 can include a sheath 280B having about two rows, each row comprisingabout four holes, each hole having a diameter of no more than about oneeighth of the diameter of the outside diameter of the sheath 280. Thetwo rows may be spaced apart circumferentially at 180 degrees, and theholes can include holes cross-drilled through both sides of the sheath280, such that each hole has a corresponding hole on the other row on anopposite side of the sheath. The sheath 280 can include sheath 280Chaving about four cross-drilled holes, each hole having a diameter of nomore than about three quarters of the diameter of the outside diameterof the sheath 280, for example. The holes can be pairs of holes, inwhich the holes of each pair have corresponding axial locations. Theholes can be arranged in two rows spaced circumferentially at 180degrees. The sheath 280 can include sheath 280D having at least aboutthree rows of at least about 3 holes, each hole having a diameter of nomore than about one quarter of the diameter of the outside diameter ofthe sheath 280. The rows can be spaced apart circumferentially at about120 degrees, for example. The sheath 280 can include sheath 280E havingat least about 40 holes, each hole having a diameter of no more thanabout one tenth of the diameter of the outside diameter of the sheath280. The sheath 280 can include sheath 280F having slots. Each of theslots can be a narrow dimension across and a long dimension across. Thelong dimension can extend axially along the sheath 280 and may extend adistance greater than the narrow dimension across. The long dimensioncan extend a distance greater than the outside diameter of the sheath280 where the slots are located, for example. The narrow dimensionacross each slot can be no more than about half of the outside diameterof the sheath, for example. The sheath 280 can be sheath 280G havingstaggered rows of holes. The plurality of openings 236 can include afirst row and a second row of cross drilled holes 236A, in which theholes of the first row are paired with the holes of the second row at acommon axial location for each pair. A third row of holes and a fourthrow of holes can include cross drilled holes 236B located at 180 degreesto each other and 90 degrees to the first row and the second row. Theaxial locations of the third and fourth rows of holes can be staggeredfrom the first and second rows of holes, such that the axial locationsof the holes 236A of the first row and second row correspond to axiallocations away from the holes 236B of the first row and the second row,for example. The sheath 280 can include sheath 280H having oval holeshaving a long dimension and a short dimension, with the long dimensionextending transverse to the axis of the sheath 280 and the shortdimension extending along the axis of the sheath 280. The oval holes canbe spaced apart and located in rows extending along the axis of thesheath as described herein, for example. The sheath 280 can includesheath 280I having elongate oval holes having the long axis of the ovalextending along the axis of the sheath and the narrow dimension of theoval extending transverse to the long axis of the sheath, for example.The sheath 280 can include sheath 280J having at least about three rowsof at least about 3 oval holes, each oval hole having a maximumdimension across of no more than about one quarter of the diameter ofthe outside diameter of the sheath 280. The rows can be spaced apartcircumferentially at about 120 degrees as described herein, for example.The sheath 280 can include sheath 280K having at least about 40 holes,each hole having a diameter of no more than about one tenth of thediameter of the outside diameter of the sheath 280. The holes can belocated on opposite sides of the sheath 280, and may comprise crossdrilled holes, for example.

The arrangement of the opening 214 from the inner needle 270 can vary aswell. For example, the opening 214 can be configured to change directionof flow from the needle 270 into the reservoir 130 to impact refillefficiency. The opening 214 can include one or more side openingslocated near the distal tip 212 of the needle 270 similar such as thatshown in FIG. 14C-14D. The openings 236 in the sheath 280, the openings214 in the needle 270, the density/viscosity of the therapeutic fluidbeing injected, the presence of one or more flow director type featureswithin the device 100 can all impact the effective flow patterns withinthe device to improve exchange efficiency.

Again with respect to FIGS. 18A-18C, the collection chamber 250 of theexchange needle apparatus 200 can have a volume (e.g., no more thanabout 200 uL, or no more than about 150 uL, or no more than about 100uL, or no more than about 50 uL) and a porous structure 256 locatedwithin at least a region of the collection chamber 250 along the ventpath. The porous structure 256 can be formed of a material having a lowresistance to air and other gasses while substantially inhibiting flowof a liquid, such as the liquid from the device 100. The material of theporous structure 256 can be a hydrophobic membrane, a fabric, a porousfabric, a semipermeable membrane, an air permeable material, a moisturevapor transfer waterproof fabric, a hydrophilic porous material, or aporous sintered material. The porous structure 256 can have a lowresistance to gas flow and a higher resistance to liquid. The liquidresistance is also greater than the liquid resistance through the porousstructure (i.e. RCE) of the device 100. Thus, if additional volume oftherapeutic fluid is injected once the exchanged liquid contacts theporous structure 256, a bolus can be released through the porousstructure device into the eye. This allows for a controlled bolus to bedriven into the eye (if desired) following the initial fill or exchangeof liquids.

A device having a pliable, expandable reservoir wall is directlyimpacted by forces of intraocular pressure (TOP) once implanted. Forexample, the eye can be viewed as a closed system in equilibrium thathas an internal pressure (intraocular pressure “TOP”) that is greaterthan atmospheric pressure. An unobstructed vent in an exchange apparatuscreates a pathway from inside the eye (higher pressure) to theatmosphere (lower pressure) upon penetration of the closed system, forexample, by injecting therapeutic into the reservoir positioned withinthe vitreous. The higher pressure of TOP presses against the pliablereservoir wall positioned within the vitreous due to this unobstructedvent to the atmosphere thereby urging the wall to collapse inward. Thus,during filling of the device, TOP can impact fill efficiency and overallpayload.

FIGS. 19A-19C illustrate fluid exchange of an implanted device 100having an expandable reservoir 130 using an exchange apparatus 200having an unrestricted vent 258 and no porous structure 256 within thecollection chamber 250. The walls of the expandable reservoir 130 arepliable such that they can be moved by forces applied to their outersurface by TOP when a path to atmospheric pressure exists, such as viathe unrestricted vent 258 of the exchange apparatus 200. Intraocularpressure can vary from patient to patient, but is generally within arange of 10 mmHg to about 21 mmHg, but can be higher than 21 mmHg inpatients suffering from ocular hypertension. The IOP pressing againstthe walls of the implanted reservoir 130 urges liquid 505 in thereservoir 130 through the openings 236, out pathway 239, and into theempty chamber 250 immediately upon insertion of the elongate structure201 through the penetrable barrier 115 into the reservoir 130 because anunrestricted path to atmospheric pressure is created (FIG. 19A). Thiscauses the walls of the reservoir 130 to collapse slightly. Air 405present within the empty collection chamber 250 escapes through ventopening 258 as the liquid 505 is expelled and begins collecting in thechamber 250. Application of positive pressure through the lumen 219 ofthe needle 270 to inject the therapeutic solution into the reservoir 130increases internal pressure within the reservoir 130 to above TOP. Theforces against the inner surface of the reservoir wall overcome theforces of TOP against the outer surface of the reservoir wall therebyurging the walls of the reservoir 130 to enlarge outward as thereservoir 130 fills with new solution (FIG. 19B). Air 405 in the chamber250 continues to escape through vent opening 258 and liquid 505 from thereservoir 130 is further urged into the openings 236, out the pathway239, and into the chamber 250. Once the application of positive pressurethrough the lumen 219 of the needle 270 to inject therapeutic into thereservoir 130 is terminated, the pressure within the reservoir 130drops. The forces against the inner surface of the reservoir wall onceagain approach the forces of TOP against the outer surface of thereservoir wall, which allows the TOP to urge the walls of the reservoir130 inward. Inward movement of the reservoir walls while the path toatmospheric pressure remains open (i.e. via the elongate structure 201)can force the newly added liquid into the openings 236, out the pathway239, and into the chamber 250 at least until the elongate structure 201is removed (FIG. 19C). Thus, unrestricted venting through vent opening258 allows for the TOP to drive the newly added therapeutic out of thereservoir 130 into the collection chamber 250 resulting in a loss indelivery payload.

To counteract the forces of TOP on the pliable, expandable reservoirwall 130, the chamber 250 can include a porous structure 256 rather thanunrestricted venting (see FIGS. 20A-20C). The porous structure 256 has aresistance sufficient to counteract the forces of TOP once filling iscomplete and maintain the increased pressure within the reservoir 130and thereby prevent loss of new solution due to partial collapse of thewall. As described above, a path to atmospheric pressure is createdimmediately upon insertion of the elongate structure 201 of the exchangeneedle apparatus 200 through the penetrable barrier 115 into thereservoir 130. The IOP pressing against the walls of the implantedreservoir 130 urges liquid 505 (i.e., a pre-existing fluid that is aliquid) in the reservoir 130 from the device 100 through the openings236, into an outlet lumen 239 that is fluidly coupled to the collectionchamber 250 (FIG. 20A). The walls of the reservoir 130 collapseslightly. The air 405 present within the empty collection chamber 250escapes through vent opening 258 and the porous structure 256 as theliquid 505 begins collecting in the chamber 250 because the porousstructure 256 has a low resistance to air. Application of positivepressure through the injection lumen 219 of the needle 270 to inject thetherapeutic solution into the reservoir 130 increases internal pressurewithin the reservoir 130 to at or above IOP. The forces against theinner surface of the reservoir wall overcome the forces of IOP againstthe outer surface of the reservoir wall thereby urging the walls of thereservoir 130 to enlarge outward as the reservoir 130 fills with newsolution (FIG. 20B). Air 405 in the collection chamber 250 continues toescape through the vent opening 258 and the porous structure 256 andliquid 505 from the reservoir 130 is further urged into the openings236, out the pathway 239, and into the collection chamber 250. Theincreased pressure during injection continues to counteract the IOPforces against the outer surface of the reservoir wall, which keeps thereservoir expanded during filling. Once the preexisting liquid 505 hasbeen exchanged with the newly injected therapeutic agent, all the air405 (i.e. a pre-existing fluid that is not a liquid) in the collectionchamber 250 has passed through the porous structure 256 and out a ventopening 258 of the apparatus and the collection chamber 250 is filledsubstantially with the newly injected therapeutic agent. The liquid 505contacts and wets the porous structure 256 of the collection chamber250. Once wetted, the porous structure 256 has a resistance to liquidflow that is sufficient to counteract the forces of intraocular pressure(TOP) on the outside surface of the pliable, expandable reservoir wall130. The liquid resistance of the wetted porous structure 256 restrictsthe flow of the liquid 505 through the porous structure 256 and furtherventing is greatly reduced. The pressure inside the device is maintainedat or higher than IOP and the reservoir wall stays expanded even whenapplication of positive pressure through the lumen 219 of the needle 270is discontinued. The retained increased pressure (i.e. at or higher thanIOP) inside the reservoir 130 prevents IOP-driven collapse of thereservoir walls (FIG. 20C). Thus, the liquid resistance of the porousstructure 256 prevents collapse of the reservoir wall 130 that wouldotherwise be caused by forces of TOP against the outside surface of thewall 130 thereby preventing the newly added solution in the reservoirfrom being driven out of the implant leading to payload loss. Theresistance to liquid flow through the wetted porous structure 256 can behigher than the resistance to liquid flow through the porous structure120 of the device. As such, if a user continues to inject therapeuticagent into the reservoir 130 through the inlet pathway, an amount ofnewly injected therapeutic agent can be passed through the porousstructure 120 of the device 100 and into the eye. This can beadvantageous for treatments in which a bolus delivery through the deviceis desirable.

The device for injecting a therapeutic agent into an ocular implant, theimplant being at least partially implanted in an eye and providing atleast a first resistance to outflow of therapeutic agent into the eye,can include an injection lumen 219, an outlet lumen 239, and acollection chamber 250. The injection lumen 219 is configured to providea pathway for injecting the therapeutic agent into the reservoir 130 ofthe ocular implant. The outlet lumen 239 is configured to provide apathway through which pre-existing fluid 505 in the ocular implant exitsthe ocular implant. The pre-existing fluid 505 in the ocular implantthat is at least partially implanted in the eye is typically a liquid.The liquid can include fluids from the patient (e.g. vitreal fluid) aswell as left over liquid from therapeutic formulation that was beingdelivered by the implant. The collection chamber 250 is fluidly coupledto the outlet lumen 239. The collection chamber 250 is configured toreceive the pre-existing fluid 505 that exits the ocular implant via theoutlet lumen 239. The collection chamber 250 provides a first fluidoutflow resistance and a second fluid outflow resistance. The firstfluid outflow resistance can be lower than the first resistance tooutflow of the implant. The second fluid outflow resistance can begreater than a force imparted onto the implant by intraocular pressure(TOP) of the eye. Injection of therapeutic agent into the ocular implantvia the injection lumen 219, for example, to refresh and refill theocular implant with new therapeutic formulation, causes the pre-existingfluid 505 to exit the ocular implant and enter the collection chamber250 via the outlet lumen 239 and causes a second pre-existing fluid 405to displace from the collection chamber 250. The second pre-existingfluid 405 in the collection chamber can be a gas, such as air or airunder vacuum. Upon displacement from the collection chamber 250 ofsubstantially all of the second pre-existing fluid 405, the second fluidoutflow resistance of the collection chamber 250 can cause a portion ofthe newly injected therapeutic agent to pass from the implant into thepatient's eye upon injection of an additional amount of the therapeuticagent into the ocular implant. Thus, the relative resistances can allowfor exchange of fluids as well as delivery of a bolus amount of thetherapeutic agent with a single penetration of the implant. The devicefor refill is particularly useful where the implant is expandable from afirst, collapsed configuration to a second, enlarged configuration,which would tend to collapse upon exposure to TOP when the ventedinjector is fluidly coupled to the reservoir's contents. A first porousstructure 256 can be operatively coupled to the collection chamber 250and provide the first fluid outflow resistance and the second fluidoutflow resistance. The first porous structure 256 operatively coupledto the collection chamber 250 can have the first fluid outflowresistance to gas outflow and the second fluid outflow resistance toliquid outflow. The implant can include a second porous structure 120that provides the first resistance to outflow. The first fluid outflowresistance of the first porous structure 256 of the collection chamber250 can be less than the first resistance provided by the second porousstructure 120 of the implant. The second fluid outflow resistance of thefirst porous structure 256 of the collection chamber 250 can be greaterthan the first resistance to outflow of the implant. The secondpre-existing fluid can be displaced from the collection chamber 250 viaa vent or a valve.

In some implementations, evacuation/filling of the reservoir 130involves aspiration. The liquid 505 in the reservoir 130 can beevacuated by application of negative forces through pathway 239 suchthat liquid 505 is drawn out of the reservoir 130 up into chamber 250.Upon evacuation of the pre-existing liquid 505 from the reservoir 130, apositive pressure can be applied to fill the reservoir with new solutionas described above. Alternatively, negative pressure can continue to beapplied through pathway 239 such that new solution is drawn into theemptied reservoir 130. As the reservoir 130 fills with new solution, theforces against the inner surface of the reservoir wall due to fluidfilling overcome the forces of TOP against the outer surface of thereservoir wall thereby urging the walls of the reservoir 130 to enlargeoutward. The pressure within the reservoir is maintained and the wallsstay expanded upon wetting of the porous structure 256 as describedabove.

The porous structure 256 can create a fixed upper limit that togetherwith wall 252 of the chamber 250 defines the volume of the chamber 250.The volume of the chamber 250 can be sufficient to collect a maximumvolume of liquid held by the device 100. The volume of the chamber 250can also be smaller than the maximum volume of liquid held by the device100 such that upon fluid exchange a controlled amount of bolusexpression occurs through the porous structure 120 of the device 100.The porous structure 256 can be a relatively rigid structure such thatupon contact with liquid 505 exiting the device 100, the porousstructure 256 resists deformation maintaining a fixed volume of thechamber 250. This prevents the structure 256 from deflecting to allowadditional liquid to enter the chamber 250 after filling that could leadto payload loss. The fixed chamber volume also allows for the controlledbolus to be delivered when used in conjunction with a fixed injectionvolume.

The geometry of the chamber 250 as well as the relative position of theporous structure 256 within the chamber 250 can vary. Generally, thegeometry and relative position of the porous structure 256 (e.g. at thehighest possible point within the chamber 250) are designed to providebetter venting of gas from the chamber 250 and predictable liquidfilling from the bottom-up. Generally, the geometry of collectionchamber 250 can direct filling to ensure the porous structure 256 iswetted by the evacuated liquid only after substantially complete airevacuation and, in turn, consistent liquid volume occurs. This ensuresthere is a “shut off” after the appropriate volume of new solution isinjected. Gravitational forces and/or capillary action can be leveragedto allow for even and predictable filling and to minimize trapping ofgas, as will be described in more detail below.

In some implementations (as shown in FIGS. 20A-20C), the porousstructure 256 encircles the needle 270 (or the longitudinal axis of theneedle 270) concentrically and engages the inner-facing walls of thechamber 250. The porous structure 256 can thereby form a cap creating afixed upper limit of the chamber 250 and together with wall 252 definethe volume of the chamber 250. The porous structure 256 can also be adiscrete structure positioned within a region of the chamber 250 as willbe described in more detail below.

FIG. 21 is a cross-sectional perspective view of an implementation of anexchange apparatus 200 configured to be used with a syringe 300 or othercontainer 310 configured to hold fluid to be delivered to the reservoir130. The exchange apparatus 200 includes a collection chamber 250configured to receive expelled fluid from the reservoir 130. Thecollection chamber 250 can be defined by a wall 252 configured tosurround the needle 270 in a generally concentric manner. The wall 252can flare out beyond a diameter of the syringe, for example, to collectlarger volumes up to about 200 uL. An upper end region of the chamber250 can be engaged with a spacer ring 265 having an inner diameter sizedto encircle the needle hub assembly 500 and an outer diameter sizedengage the wall 252. The spacer ring 265 forms a cap creating a fixedupper limit of the chamber 250 that together with wall 252 defines thevolume of the chamber 250. The porous structure 256 can be installedwithin a region of the spacer ring 265 near the upper limit of thechamber 250. As previously described, the porous structure 256 can be arelatively rigid structure formed of a material having a low resistanceto gas flow (e.g. air) and high resistance to liquid therebysubstantially inhibiting flow of a liquid through it. The porousstructure 256 is configured to balance the forces of TOP on the pliablereservoir walls of the device preventing collapse after filling therebypreventing payload loss.

FIG. 22 shows a perspective view of another implementation of theexchange apparatus 200 having a collection chamber 250 that is offsetrelative to the axis 202 of the needle 270 (or the injection lumen ofthe needle 270). A concentrically positioned collection chamber 250relative to the exchange needle 270 can impact a user's view of thedevice, especially where the chamber 250 has a high volume capacity(e.g. greater than 200 ul). The collection chamber 250 can be off-setfrom the axis 202 of the exchange needle 270 to mitigate issues with thechamber 250 obstructing a user's view of the device during penetration.Additionally, the body of the collection chamber 250 can incorporate oneor more grip features 253 and/or be ergonomically shaped to assist inhandling. As with other implementations, the collection chamber 250 canincorporate a porous structure 256, for example, near an upper limit ofthe collection chamber 250.

FIG. 23 shows a partially exploded view of another implementation of anexchange apparatus 200 having an offset collection chamber 250. A user'sview of the needle tip (not shown) can be enhanced by modifying theshape of the needle cannula passage 267. For example, the needle cannulapassage 267 can extend along a first axis A at a proximal end region andextend along a second axis B at a distal end region near the needle tip.As such, the needle cannula is routed from the first axis A to thesecond axis A such that is it routed away from the offset body 251 andthe needle tip is no longer concentric to the hub assembly 500 or thesyringe barrel connected to the hub assembly 500. Fluid expelled fromthe device into a return pathway is directed into the narrow collectionchamber 250 through opening 285. In this implementation, the collectionchamber 250 can be a tubular structure 269 having a lumen extendingbetween the opening 285 into the tubular structure 269 and terminatingat the porous element 256. Fluid expelled from the device throughopening 285 enters the lumen of the tubular structure 269. The tubularstructure 269 can have a relatively uniform inner diameter over itsentire length. Inner diameter and length of the tubular structure 269can vary depending on the overall volume capacity desired. The tubularstructure 269 can be between 0.5 inches and 3.0 inches long and have aninner diameter between 0.125 inches and 0.5 inches. The tubularstructure 269 can have an inner diameter such that capillary action canassist in pulling the exchanged liquid expelled from the reservoir 130of the device 100 into and up through the lumen. Depending on the lengththe tubular structure 269 the end of the tubing away from the opening285 into the lumen (i.e. within the body of the exchange apparatus) canbe coiled. The number of coils varies with the length of the tubing.Thus, the coiled tube style collection chamber 250 can have a widerrange in volume capacity while maintaining generally the same formfactor. The coiled tube style collection chamber 250 provides for auniform and controlled fill pattern, minimizing the risk of trapping airwithin the chamber 250 during exchange. Trapped air within thecollection chamber 250 can impact the final fluid volume achieved withinthe reservoir of the device.

FIGS. 24A-24D illustrate another implementation of an exchange apparatus200 having an off-set collection chamber 250. FIG. 24A is a transparentside view, FIG. 24B is a transparent top plan view, FIG. 24C is a sideview, and FIG. 24D is a side cut-away view. The collection chamber 250can have a narrow, tubular distal end region 275 that widens or enlargesproximally into a larger diameter proximal end region 277 of thecollection chamber 250. The narrow distal end region 275 can begenerally tubular for at least a length. Fluid expelled from thereservoir 130 of the device 100 enters the distal end region 275 via theopening 285. The fluid entering the distal end region 275 of thecollection chamber 250 through the opening 285 is funneled through thecollection chamber 250 towards the porous element 256 mounted at theupper or proximal end of the collection chamber 250. The porousstructure 256 can be mounted according to a variety of configurations asdescribed elsewhere herein. As described elsewhere herein, the porousstructure 256 is configured to balance the forces of IOP on the pliablereservoir walls of the device preventing collapse after filling therebypreventing payload loss. The inner diameter of the distal end region 275of the collection chamber 250 can be sized to provide for a uniform andcontrolled fill pattern that minimizes the risk of trapping air withinthe chamber 250 during exchange. The off-set configuration of the body251 within which the collection chamber 250 is housed is streamlined andcan wrap around the syringe barrel to minimize overall size forincreased visibility of the treatment device during use. The body 251 ofthe exchange apparatus 200 tapers towards the needle tip (not shown) atan angle relative to the axis 202 of the cannula that improvesvisibility during use. The needle tip can be concentric or eccentric tothe needle luer or the syringe barrel as described elsewhere herein.

Again with respect to FIGS. 24A-24D, the body 251 extends a firstdistance past a region where the needle hub assembly 500 couples with asyringe barrel 300. The body 251 of the collection chamber 250 can bearranged side-by-side with the syringe barrel 300. The size of thecollection chamber body 251 can vary. FIG. 25 illustrates animplementation of an exchange apparatus 200 having an offset collectionchamber 250 designed for larger capacity, for example a volume of about200 ul, 300 ul or 400 ul. The overall configuration of the collectionchamber 250 in which a distal end region 275 near the opening 258 intothe collection chamber 250 is narrow and widens towards the proximal endregion 277 directing fluid up to the porous structure 256 near an upperlimit of the chamber 250. However, the larger capacity of the collectionchamber 250 is provided for by extending a length of the body 251 withinwhich the collection chamber 250 is housed. The longer collectionchamber body 251 can align side-by-side with the syringe barrel 300. Itshould be appreciated that any of a variety of collection chambervolumes is considered herein, particularly for filling another type ofimplanted drug delivery device that is not limited by implantationwithin the vitreous.

The treatment devices described herein can be refilled after a period oftime. The septum of the treatment device can be penetrated during refillwith a refill needle, as described above, or for example such as thatdescribed in U.S. Pat. No. 9,033,911 or in U.S. Publication No.2013/0165860, which are each incorporated by reference herein. Therefill needle and the fill needle can be the same type of needle or canbe distinct from one another. For example, the fill needle may or maynot incorporate features to visualize filling whereas the refill needledoes incorporate such features.

The fill needle and/or refill needle used in conjunction with the deviceimplementations having elongated neck regions and/or redundantpenetrable barriers as described in U.S. Provisional Application Ser.No. 62/318,582, filed Apr. 5, 2016, which is incorporated herein byreference thereto, may be longer than needles used in conjunction withdevice implementations having shorter neck regions. In someimplementations, such as when redundant barrier systems areincorporated, the needle may include one or more reinforcementstructures to accommodate the longer travel through the septum or aconcentration of return holes near the distal end of the refill needlein order to refill the system efficiently. For example, to access thereservoir of a device having an elongated upper end region andincorporating, for example, a redundant septum or a penetrable elementthat does not reside within the proximal portion of the neck a needlemay incorporate one or more features to provide for better penetrationincluding, but not limited to a longer length, a reinforcement structuresurrounding at least a region of its length, and/or concentration ofreturn fluid holes near the distal end of the needle.

Once the expanded volume of the implanted reservoir is achieved, thedevice can be refilled at predictable intervals (e.g. every 3, 4, 5, 6months or as along as every 12 months). However, changing the volume ofthe expanded device once implanted in the eye may not be desirable (e.g.movement in the eye once implanted may lead to potential trauma tosurrounding structures or fluctuations in intraocular pressure) and isthus something to be avoided. The treatment devices described hereinonce implanted and expanded can maintain a consistent volume such thatthe outer diameter or contour of the reservoir does not changesubstantially throughout the use of the device and regardless of fillstatus. Further, the treatment devices described herein can maintainsubstantially the same expanded shape. For example, drug passivelydiffuses through the porous drug delivery element and out of theexpanded reservoir over time. Despite this drug release into the eye,the expanded reservoir can remain filled with fluid, for example, fluidthat enters the reservoir from the vitreous and drug formulation fluidremaining in the reservoir. The reservoir material can be formed of asubstantially non-compliant material that tends to maintain its physicalstructure regardless of whether the interior of the reservoir is filledwith drug. Further, refill of the treatment devices described herein canbe performed such that a negative pressure and/or an excessive positivepressure do not build within it.

FIGS. 26A-26C show an implementation of an exchange apparatus 200 havingan elongate structure 201 having a needle 270 extending through aremovable sheath 280 and a collection chamber 250 that is removable fromthe exchange needle apparatus 200. As described elsewhere herein, theexchange needle apparatus 200 can include a locking connector 290 near aproximal end configured to couple to a syringe 300. Also as describedelsewhere herein, the needle 270 and sheath 280 are configured to injectnew material into the device 100 while simultaneously directingpre-existing material from the device 100 into the collection chamber250 using positive pressure. The needle 270 of the elongate structure201 can include an inner channel 219 coupled at its proximal end to thesyringe 300 or other container holding the therapeutic fluid to beinjected into the device. The channel 219 can extend to a distal opening214 through which the therapeutic fluid can exit the lumen into thedevice 100. A sheath 280 having one or more openings 236 can surround atleast a portion of the needle 270 creating a channel 239 along at leasta portion of the outer surface of the needle 270 leading toward thecollection chamber 250.

The collection chamber 250 can be defined by an impermeable wall 252around at least a portion of the chamber 250. A first plug 430 formed ofa penetrable barrier material such as an elastomeric septum can bepositioned within a proximal opening to the chamber 250. A second plug420 formed of a penetrable barrier material can be positioned at adistal end of the chamber 250 such that the chamber 250 is sealed oneither end by the plugs 430, 420 (see FIG. 26C). At least the needle 270of the elongate structure 201 can extend through the distal plug 420.The sheath 280 can extend from and be supported by a distal end of thewall 252 such that the sheath 280 remained attached to the wall 252 uponremoval of the collection chamber 250 from the exchange apparatus 200.The plug 420 can be placed over the sheath 280 and the needle 270extending through the sheath prior to removal of the needle 270. Theplug 420 can thereby inhibit leakage of the implantable device fluid 262and sample fluid 264 from the distal opening of the chamber 250. A cap435 can be positioned over the outer surface of plug 430 (FIG. 26C). Theplug 430 and cap 435 can inhibit one or more of evaporation or leakageof the implantable device fluid 262 comprising sample fluid 264.

FIGS. 27A-27D illustrate another implementation of an exchange needleapparatus 200 having a collection chamber 250 that is removable from theexchange needle apparatus 200. The collection chamber 250 can be definedby an impermeable wall 252 around at least a portion of the chamber 250.A first plug 430 formed of a penetrable barrier material such as anelastomeric septum can be positioned at a proximal end of the chamber250 and a second plug 420 can be positioned at a distal end of thechamber 250 such that the chamber 250 is sealed on either end by theplugs 430, 420. At least the needle 270 of the elongate structure 201can extend through the first and second plugs 430, 420 (see FIG. 27B).As described elsewhere herein, a porous structure 256 can be positionedwithin the proximal end of the collection chamber 250 forming a proximalcap feature for restricting the venting of the exchange needle apparatus200 during filling of the expandable reservoir 130. This porousstructure 256 can be located distal to the proximal plug 430 such thatat least the needle 270 of the elongate structure 201 additionallyextends through the porous structure 256. FIG. 27C is a detail viewshowing the needle 270 of the elongate structure 201 extending throughan outer sheath 280 and piercing the distal plug 420. Openings into 236and from the outer sheath 280 allow the exchanged liquid to drain intothe chamber 250.

The collection chamber 250 can be removably coupled to the exchangeapparatus 200 by any of a variety of mechanisms including annularsnap-fit or threaded couplings. In some implementations, the collectionchamber 250 can be removed from the exchange apparatus 200 by way of athreaded coupling. FIG. 27D is a view of the separated container 400having the collection chamber 250 enclosed by two plugs 430, 420 leavingbehind the needle hub assembly 500 including the elongate structure 201and connector 290. Fluid can remain contained within the chamber 250with both plugs 430, 420 resealed after withdrawal of the elongatestructure 201. A distal end region 565 of the needle hub assembly 500can be threaded and a proximal end region 465 of the sample container400 can be correspondingly threaded such that the distal end region 565and the proximal end region 465 couple together in threaded engagement.The thread of the needle hub assembly 500 can be on an outer surface ofthe distal end region 565 and the thread of the container 400 can be onan inner surface of the proximal end region 465 such that the proximalend region 465 receives the distal end region 565 of the needle hubassembly 500 therein.

The sample container 400 including the sealed collection chamber 250upon separation from the remainder of the hub assembly 500 (as shown inFIG. 26B and FIG. 27D) can be transported, for example, to a labfacility or other location for further processing. One or both of theplugs 420, 430 can be penetrated in order to withdraw the sample fluid264 within the chamber 250 such as by piercing the plugs 420, 430 with aneedle to recover the fluid within a syringe. Alternatively oradditionally, the sample container 400 can include a penetrablestructure 259 within another area such as the wall 252 of the chamber250 that can be penetrated by a needle-type device to draw a sample fromthe receiver chamber 250. The structure 259 can include one or morere-sealable materials suitable for penetration with a needle such as oneor more of rubber or silicone elastomer. The structure 259 can alsoinclude one or more materials such as a fabric, a porous fabric, asemipermeable membrane, an air permeable material, a moisture vaportransfer waterproof fabric, a hydrophilic porous material, or a porousmaterial or a porous sintered material. As described elsewhere herein,the wall 252 of the collection chamber 250 can be transparent ortranslucent such that a volume of material held within the collectionchamber 250 is discernable to the user. The sample container 400 canhave one or more shapes such as annular, spherical, cubic, ellipsoidal,or oval.

Indications

The treatment devices described herein can be used to treat and/orprevent a variety of other ocular conditions besides glaucoma, includingbut not limited to dry or wet age-related macular degeneration (AMD),neuroprotection of retinal ganglion cells, cataract or presbyopiaprevention, cancers, angiogenesis, neovascularization, choroidalneovascularization (CNV) lesions, retinal detachment, proliferativeretinopathy, proliferative diabetic retinopathy, degenerative disease,vascular diseases, occlusions, infection caused by penetrating traumaticinjury, endophthalmitis such as endogenous/systemic infection,post-operative infections, inflammations such as posterior uveitis,retinitis or choroiditis and tumors such as neoplasms andretinoblastoma. Still further conditions that can be treated and/orprevented using the devices and methods described herein, include butare not limited to hemophilia and other blood disorders, growthdisorders, diabetes, leukemia, hepatitis, renal failure, HIV infection,hereditary diseases such as cerebrosidase deficiency and adenosinedeaminase deficiency, hypertension, septic shock, autoimmune diseasessuch as multiple sclerosis, Graves' disease, systemic lupuserythematosus and rheumatoid arthritis, shock and wasting disorders,cystic fibrosis, lactose intolerance, Crohn's disease, inflammatorybowel disease, gastrointestinal or other cancers, degenerative diseases,trauma, multiple systemic conditions such as anemia.

Therapeutics

Examples of therapeutic agents that may be delivered by the treatmentdevices described herein and/or are described in the applicationsincorporated by reference herein are provided below and in Table 1 ofU.S. application Ser. No. 14/937,784, published as U.S. 2016/0128867,which is incorporated herein in its entirety.

Therapeutics that can be delivered from the devices described hereininclude but are not limited to triamcinolone acetonide, bimatoprost orthe free acid of bimatoprost, latanoprost or the free acid or salts ofthe free acid of latanoprost, ranibizumab, travoprost or the free acidor salts of the free acid of travoprost, timolol, levobunalol,brimonidine, dorzolamide, brinzolamide. Additional examples oftherapeutic agents that may be delivered by the therapeutic deviceinclude antibiotics such as tetracycline, chlortetracycline, bacitracin,neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline,chloramphenicol kanamycin, rifampicin, ciprofloxacin, tobramycin,gentamycin, erythromycin and penicillin; antifungals such asamphotericin B and miconazole; anti-bacterials such as sulfonamides,sulfadiazine, sulfacetamide, sulfamethizole and sulfisoxazole,nitrofurazone and sodium propionate; antivirals such as idoxuridine,trifluorotymidine, acyclovir, ganciclovir and interferon;antiallergenics such as sodium cromoglycate, antazoline, methapyriline,chlorpheniramine, pyrilamine, cetirizine and prophenpyridamine;anti-inflammatories such as hydrocortisone, hydrocortisone acetate,dexamethasone, dexamethasone 21-phosphate, fluocinolone, medrysone,prednisolone, prednisolone 21-phosphate, prednisolone acetate,fluoromethalone, betamethasone, and triamcinolone; non-steroidalanti-inflammatories such as salicylate, indomethacin, ibuprofen,diclofenac, flurbiprofen and piroxicam; decongestants such asphenylephrine, naphazoline and tetrahydrozoline; miotics andanticholinesterases such as pilocarpine, salicylate, acetylcholinechloride, physostigmine, eserine, carbachol, diisopropylfluorophosphate, phospholine iodide and demecarium bromide; mydriaticssuch as atropine sulfate, cyclopentolate, homatropine, scopolamine,tropicamide, eucatropine and hydroxyamphetamine; sypathomimetics such asepinephrine; antineoplastics such as carmustine, cisplatin andfluorouracil; immunological drugs such as vaccines and immunestimulants; hormonal agents such as estrogens, estradiol,progestational, progesterone, insulin, calcitonin, parathyroid hormoneand peptide and vasopressin hypothalamus releasing factor; betaadrenergic blockers such as timolol maleate, levobunolol HCl andbetaxolol HCl; growth factors such as epidermal growth factor,fibroblast growth factor, platelet derived growth factor, transforminggrowth factor beta, somatotropin and fibronectin; carbonic anhydraseinhibitors such as dichlorophenamide, acetazolamide and methazolamideand other drugs such as prostaglandins, antiprostaglandins andprostaglandin precursors. Other therapeutic agents known to thoseskilled in the art which are capable of controlled, sustained releaseinto the eye in the manner described herein are also suitable for use inaccordance with embodiments of the devices described herein.

The therapeutic agent can also include one or more of the following:abarelix, abatacept, abciximab, adalimumab, aldesleukin, alefacept,alemtuzumab, alpha-1-proteinase inhibitor, alteplase, anakinra,anistreplase, antihemophilic factor, antithymocyte globulin, aprotinin,arcitumomab, asparaginase, basiliximab, becaplermin, bevacizumab,bivalirudin, botulinum toxin type A, botulinum toxin type B,brolucizumab, capromab, cetrorelix, cetuximab, choriogonadotropin alfa,coagulation factor IX, coagulation factor VIIa, collagenase,corticotropin, cosyntropin, cyclosporine, daclizumab, darbepoetin alfa,defibrotide, denileukin diftitox, desmopressin, dornase alfa,drotrecogin alfa, eculizumab, efalizumab, enfuvirtide, epoetin alfa,eptifibatide, etanercept, exenatide, felypressin, filgrastim,follitropin beta, galsulfase, gemtuzumab ozogamicin, glatiramer acetate,glucagon recombinant, goserelin, human serum albumin, hyaluronidase,ibritumomab, idursulfase, immune globulin, infliximab, insulin glarginerecombinant, insulin lyspro recombinant, insulin recombinant, insulin,porcine, interferon alfa-2a, recombinant interferon alfa-2b, recombinantinterferon alfa con-1, interferon alfa-nl, interferon alfa-n3,interferon beta-1b, interferon gamma-1b, lepirudin, leuprolide, lutropinalfa, mecasermin, menotropins, muromonab, natalizumab, nesiritide,octreotide, omalizumab, oprelvekin, ospA lipoprotein, oxytocin,palifermin, palivizumab, panitumumab, pegademase bovine, pegaptanib,pegaspargase, pegfilgrastim, peginterferon alfa-2a, peginterferonalfa-2b, pegvisomant, pramlintide, ranibizumab, rasburicase, reteplase,rituximab, salmon calcitonin, sargramostim, secretin, sermorelin, serumalbumin iodonated, somatropin recombinant, streptokinase, tenecteplase,teriparatide, thyrotropin alfa, tositumomab, trastuzumab,urofollitropin, urokinase, or vasopressin.

The therapeutic agent can include one or more of compounds that act bybinding members of the immunophilin family of cellular proteins. Suchcompounds are known as “immunophilin binding compounds” Immunophilinbinding compounds include but are not limited to the “limus” family ofcompounds. Examples of limus compounds that may be used include but arenot limited to cyclophilins and FK506-binding proteins (FKBPs),including sirolimus (rapamycin) and its water soluble analog SDZ-RAD,tacrolimus, everolimus, pimecrolimus, CCI-779 (Wyeth), AP23841 (Ariad),and ABT-578 (Abbott Laboratories). The limus family of compounds may beused in the compositions, devices and methods for the treatment,prevention, inhibition, delaying the onset of, or causing the regressionof angiogenesis-mediated diseases and conditions of the eye, includingchoroidal neovascularization. The limus family of compounds may be usedto prevent, treat, inhibit, delay the onset of, or cause regression ofAMD, including wet AMD. Rapamycin may be used to prevent, treat,inhibit, delay the onset of, or cause regression ofangiogenesis-mediated diseases and conditions of the eye, includingchoroidal neovascularization. Rapamycin may be used to prevent, treat,inhibit, delay the onset of, or cause regression of AMD, including wetAMD.

The therapeutic agent can include one or more of: pyrrolidine,dithiocarbamate (NF.kappa.B inhibitor); squalamine; TPN 470 analogue andfumagillin; PKC (protein kinase C) inhibitors; Tie-1 and Tie-2 kinaseinhibitors; proteosome inhibitors such as bortezomib, for injection;ranibuzumab and other antibodies directed to the same target;pegaptanib; vitronectin receptor antagonists, such as cyclic peptideantagonists of vitronectin receptor-type integrins; .alpha.-v/.beta.-3integrin antagonists; .alpha.-v/.beta.-1 integrin antagonists;thiazolidinediones such as rosiglitazone or troglitazone; interferon,including .gamma.-interferon or interferon targeted to CNV by use ofdextran and metal coordination; pigment epithelium derived factor(PEDF); endostatin; angiostatin; tumistatin; canstatin; anecortaveacetate; acetonide; triamcinolone; tetrathiomolybdate; RNA silencing orRNA interference (RNAi) of angiogenic factors, including ribozymes thattarget VEGF expression; 13-cis retinoic acid; ACE inhibitors, includingbut not limited to quinopril, captopril, and perindozril; inhibitors ofmTOR (mammalian target of rapamycin); 3-aminothalidomide;pentoxifylline; 2-methoxyestradiol; colchicines; AMG-1470;cyclooxygenase inhibitors such as nepafenac, rofecoxib, diclofenac,rofecoxib, NS398, celecoxib, vioxx, and(E)-2-alkyl-2(4-methanesulfonylphenyl)-1-phenylethene; t-RNA synthasemodulator; metalloprotease 13 inhibitor; acetylcholinesterase inhibitor;potassium channel blockers; endorepellin; purine analog of6-thioguanine; cyclic peroxide ANO-2; (recombinant) arginine deiminase;epigallocatechin-3-gallate; cerivastatin; analogues of suramin; VEGFtrap molecules; apoptosis inhibiting agents; verteporfin; snET2 andother photo sensitizers, which may be used with photodynamic therapy(PDT); inhibitors of hepatocyte growth factor (antibodies to the growthfactor or its receptors, small molecular inhibitors of the c-mettyrosine kinase, truncated versions of HGF e.g. NK4).

The therapeutic agent can include inhibitors of VEGF receptor kinase;inhibitors of VEGFA, VEGFC, VEGFD, bFGF, PDGF, Ang-1, Ang-2, PDGFR,cKIT, FGF, BDGF, mTOR, αvβ3, αvβ5, α5β1 integrin, and alpha2 adrenergicreceptor; inhibitors of complement factor B (e.g. TA106), complementfactor D (CFD) (lampalizumab/TNX-234), C3 (e.g. APL-2, novel compstatinanalogs), C5 (e.g. eculizumab, ARC1905, ALN-CC5), C5a (e.g. JPE-1375),and tubulin; AAV-CD56 The therapeutic agent can also include ComplementFactor H (CFH), engineered mini-CFH, or recombinant CFH (rCFH).

The therapeutic agent can include a combination with other therapeuticagents and therapies, including but not limited to agents and therapiesuseful for the treatment of angiogenesis or neovascularization,particularly CNV. Non-limiting examples of such additional agents andtherapies include pyrrolidine, dithiocarbamate (NF.kappa.B inhibitor);squalamine; TPN 470 analogue and fumagillin; PKC (protein kinase C)inhibitors; Tie-1 and Tie-2 kinase inhibitors; inhibitors of VEGFreceptor kinase; proteosome inhibitors such as bortezomib, forinjection; ranibizumab and other antibodies directed to the same target;pegaptanib; vitronectin receptor antagonists, such as cyclic peptideantagonists of vitronectin receptor-type integrins; .alpha.-v/.beta.-3integrin antagonists; .alpha.-v/.beta.-1 integrin antagonists;thiazolidinediones such as rosiglitazone or troglitazone; interferon,including .gamma-interferon or interferon targeted to CNV by use ofdextran and metal coordination; pigment epithelium derived factor(PEDF); endostatin; angiostatin; tumistatin; canstatin; anecortaveacetate; acetonide; triamcinolone; tetrathiomolybdate; RNA silencing orRNA interference (RNAi) of angiogenic factors, including ribozymes thattarget VEGF expression; 13-cis retinoic acid; ACE inhibitors, includingbut not limited to quinopril, captopril, and perindozril; inhibitors ofmTOR (mammalian target of rapamycin); 3-aminothalidomide;pentoxifylline; 2-methoxyestradiol; colchicines; AMG-1470;cyclooxygenase inhibitors such as nepafenac, rofecoxib, diclofenac,rofecoxib, NS398, celecoxib, vioxx, and(E)-2-alkyl-2(4-methanesulfonylphenyl)-1-phenylethene; t-RNA synthasemodulator; metalloprotease 13 inhibitor; acetylcholinesterase inhibitor;potassium channel blockers; endorepellin; purine analog of6-thioguanine; cyclic peroxide ANO-2; (recombinant) arginine deiminase;epigallocatechin-3-gallate; cerivastatin; analogues of suramin; VEGFtrap molecules; inhibitors of hepatocyte growth factor (antibodies tothe growth factor or its receptors, small molecular inhibitors of thec-met tyrosine kinase, truncated versions of HGF e.g. NK4); apoptosisinhibiting agents; snET2 and other photo sensitizers with photodynamictherapy (PDT); and laser photocoagulation.

Prostaglandin analogues (PGAs) can be used to increase outflow ofaqueous through the ciliary body and/or the trabecular meshworkincluding travaprost (0.004%), bimatoprost (0.03%, 0.01%), tafluprost(0.0015%), and latanoprost (0.005%). Beta blockers can be used to reduceaqueous fluid production by the ciliary body. Drugs in this classinclude timolol (0.5%). Carbonic anhydrase inhibitors can be used toreduce aqueous fluid production by the ciliary body as well. Drugs inthis class include brinzolamide (1%), methazolamide, dorzolamide (2%),and acetazolamide. Alpha antagonists can be used to reduce aqueous fluidproduction by the ciliary body and increase outflow through thetrabecular meshwork. Thus, the drug targets tissues located in both theanterior chamber and the posterior chamber and as such the devices canbe implanted in either location to achieve a therapeutic result. Drugsin this class include brimonidine (0.1%, 0.15%) and apraclonidine (0.5%,1.0%). Commercially available combinations of therapeutics consideredherein include brimonidine tartrate/timolol maleate ophthalmic solution,and dorzolamide hydrochloride-timolol maleate ophthalmic solution.Further, other sustained release therapeutics considered herein includesubconjunctival latanoprost, intracameral bimatoprost, and intravitrealbrimonidine.

Various pharmaceutically acceptable carriers for the therapeutic agentsdescribed herein can include such as, for example, solids such asstarch, gelatin, sugars, natural gums such as acacia, sodium alginateand carboxymethyl cellulose; polymers such as silicone rubber; liquidssuch as sterile water, saline, dextrose, dextrose in water or saline;condensation products of castor oil and ethylene oxide, liquid glyceryltriester of a lower molecular weight fatty acid; lower alkanols; oilssuch as corn oil, peanut oil, sesame oil, castor oil, and the like, withemulsifiers such as mono- or di-glyceride of a fatty acid, or aphosphatide such as lecithin, polysorbate 80, and the like; glycols andpolyalkylene glycols; aqueous media in the presence of a suspendingagent, for example, sodium carboxymethylcellulose, sodium hyaluronate,sodium alginate, poly(vinyl pyrrolidone) and similar compounds, eitheralone, or with suitable dispensing agents such as lecithin,polyoxyethylene stearate and the like. The carrier may also containadjuvants such as preserving, stabilizing, wetting, emulsifying agentsor other related materials.

Materials

Generally, the components of the devices described herein are fabricatedof materials that are biocompatible and preferably insoluble in the bodyfluids and tissues that the device comes into contact with. Thematerials generally do not cause irritation to the portion of the eyethat it contacts. Materials may include, by way of example, variouspolymers including, for example, silicone elastomers and rubbers,polyolefins, polyurethanes, acrylates, polycarbonates, polyamides,polyimides, polyesters, and polysulfones. One or more components of thedevices described herein can be fabricated of a permeable materialincluding, but not limited to, polycarbonates, polyolefins,polyurethanes, copolymers of acrylonitrile, copolymers of polyvinylchloride, polyamides, polysulphones, polystyrenes, polyvinyl fluorides,polyvinyl alcohols, polyvinyl esters, polyvinyl butyrate, polyvinylacetate, polyvinylidene chlorides, polyvinylidene fluorides, polyimides,polyisoprene, polyisobutylene, polybutadiene, polyethylene, polyethers,polytetrafluoroethylene, polychloroethers, polymethylmethacrylate,polybutylmethacrylate, polyvinyl acetate, nylons, cellulose, gelatin,silicone rubbers and porous rubbers. One or more components of thedevices described herein can be fabricated of a nonbiodegradablepolymer, including but not limited to polymethylmethacrylate, a siliconeelastomer, or silicone rubber. Other suitable non-erodible,biocompatible polymers which may be used in fabricating the devicesdescribed herein may include polyolefins such as polypropylene andpolyethylene, homopolymers, and copolymers of vinyl acetate such asethylene vinyl acetate copolymer, polyvinylchlorides, homopolymers andcopolymers of acrylates such as polyethylmethacrylate, polyurethanes,polyvinylpyrrolidone, 2-pyrrolidone, polyacrylonitrile butadiene,polycarbonates, polyamides, fluoropolymers such aspolytetrafluoroethylene and polyvinyl fluoride, polystyrenes,homopolymers and copolymers of styrene acrylonitrile, cellulose acetate,homopolymers and copolymers of acrylonitrile butadiene styrene,polymethylpentene, polysulfones, polyesters, polyimides, natural rubber,polyisobutylene, polymethylstyrene and other similar non-erodiblebiocompatible polymers.

One or more of the components of the devices described herein can befabricated of a substantially non-compliant material that can beexpanded to a particular shape. One or more of the components of thedevices described herein can be fabricated of a rigid, non-pliablematerial. One or more of the components of the devices described hereincan be fabricated of a shape memory material and/or superelasticmaterial including, but not limited to shape memory alloys (SMA) likeNitinol (Ni—Ti alloy) and shape memory polymers (SMP) like AB-polymernetworks based on oligo(e-caprolactone) dimethacrylates and n-butylacrylate. Shape memory alloys generally have at least two phases: (1) amartensite phase, which has a relatively low tensile strength and whichis stable at relatively low temperatures, and (2) an austenite phase,which has a relatively high tensile strength and which is stable attemperatures higher than the martensite phase. The shape memorycharacteristics are imparted on the material by heating the material toa temperature above the temperature at which the austenite phase isstable. While the material is heated to this temperature, the device isheld in the “memory shape”, which is shape that is desired to be“remembered”.

In various implementations, description is made with reference to thefigures. However, certain implementations may be practiced without oneor more of these specific details, or in combination with other knownmethods and configurations. In the description, numerous specificdetails are set forth, such as specific configurations, dimensions, andprocesses, in order to provide a thorough understanding of theimplementations. In other instances, well-known processes andmanufacturing techniques have not been described in particular detail inorder to not unnecessarily obscure the description. Reference throughoutthis specification to “one embodiment,” “an embodiment,” “oneimplementation, “an implementation,” or the like, means that aparticular feature, structure, configuration, or characteristicdescribed is included in at least one embodiment or implementation.Thus, the appearance of the phrase “one embodiment,” “an embodiment,”“one implementation, “an implementation,” or the like, in various placesthroughout this specification are not necessarily referring to the sameembodiment or implementation. Furthermore, the particular features,structures, configurations, or characteristics may be combined in anysuitable manner in one or more implementations.

The use of relative terms throughout the description may denote arelative position or direction or orientation and is not intended to belimiting. For example, “distal” may indicate a first direction away froma reference point. Similarly, “proximal” may indicate a location in asecond direction opposite to the first direction. Use of the terms“front,” “side,” and “back” as well as “anterior,” “posterior,”“caudal,” “cephalad” and the like or used to establish relative framesof reference, and are not intended to limit the use or orientation ofany of the devices and/or systems to a specific configuration describedin the various implementations.

While this specification contains many specifics, these should not beconstrued as limitations on the scope of what is claimed or of what maybe claimed, but rather as descriptions of features specific toparticular embodiments. Certain features that are described in thisspecification in the context of separate embodiments can also beimplemented in combination in a single embodiment. Conversely, variousfeatures that are described in the context of a single embodiment canalso be implemented in multiple embodiments separately or in anysuitable sub-combination. Moreover, although features may be describedabove as acting in certain combinations and even initially claimed assuch, one or more features from a claimed combination can in some casesbe excised from the combination, and the claimed combination may bedirected to a sub-combination or a variation of a sub-combination.Similarly, while operations are depicted in the drawings in a particularorder, this should not be understood as requiring that such operationsbe performed in the particular order shown or in sequential order, orthat all illustrated operations be performed, to achieve desirableresults. Only a few examples and implementations are disclosed.Variations, modifications and enhancements to the described examples andimplementations and other implementations may be made based on what isdisclosed.

In the descriptions above and in the claims, phrases such as “at leastone of” or “one or more of” may occur followed by a conjunctive list ofelements or features. The term “and/or” may also occur in a list of twoor more elements or features. Unless otherwise implicitly or explicitlycontradicted by the context in which it is used, such a phrase isintended to mean any of the listed elements or features individually orany of the recited elements or features in combination with any of theother recited elements or features. For example, the phrases “at leastone of A and B;” “one or more of A and B;” and “A and/or B” are eachintended to mean “A alone, B alone, or A and B together.” A similarinterpretation is also intended for lists including three or more items.For example, the phrases “at least one of A, B, and C;” “one or more ofA, B, and C;” and “A, B, and/or C” are each intended to mean “A alone, Balone, C alone, A and B together, A and C together, B and C together, orA and B and C together.”

Use of the term “based on,” above and in the claims is intended to mean,“based at least in part on,” such that an unrecited feature or elementis also permissible.

1.-20. (canceled)
 21. An exchange device for use with a syringe, theexchange device comprising: a needle hub assembly configured to couplewith the syringe; a needle coupled to and projecting distal from theneedle hub assembly, the needle comprising: an injection lumenconfigured to provide a pathway for injecting a therapeutic agent intoan ocular implant, the ocular implant at least partially implanted in aneye and providing at least a first resistance to outflow of therapeuticagent into the eye; and an outlet lumen configured to provide a pathwaythrough which liquid in the ocular implant exits the ocular implant asit is displaced by the therapeutic agent; and a collection chamber influid communication with the outlet lumen so as to receive the liquiddisplaced from the ocular implant via the outlet lumen, wherein thecollection chamber comprises a spacer ring positioned within an upperend region of the collection chamber, the spacer ring having an innerdiameter sized to encircle a portion of the needle hub assembly and anouter diameter sized to engage a wall of the collection chamber, whereina porous structure is positioned within a region of the spacer ring. 22.The exchange device of claim 21, wherein the spacer ring forms a capcreating a fixed upper limit of the collection chamber that togetherwith the wall defines a volume of the collection chamber.
 23. Theexchange device of claim 21, wherein the wall surrounds at least aportion of the needle in a concentric manner.
 24. The exchange device ofclaim 21, wherein the wall flares out beyond a diameter of the syringe.25. The exchange device of claim 21, wherein the volume of thecollection chamber is up to about 200 uL.
 26. The exchange device ofclaim 21, wherein the porous structure comprises a rigid structureformed of a material having a low resistance to gas flow and a highresistance to liquid.
 27. The exchange device of claim 21, wherein thecollection chamber provides a first fluid outflow resistance to gasoutflow and a second fluid outflow resistance to liquid outflow, whereinthe first fluid outflow resistance is lower than the first resistance tooutflow of the ocular implant, and the second fluid outflow resistanceis greater than a force imparted onto the ocular implant by intraocularpressure of the eye, and wherein injection of therapeutic agent into theocular implant via the injection lumen causes the liquid to exit theocular implant and enter the collection chamber via the outlet lumen anddisplaces a fluid from the collection chamber.
 28. The exchange deviceof claim 27, wherein the fluid is air.
 29. The exchange device of claim27, wherein the fluid is displaced from the collection chamber via avent.
 30. The exchange device of claim 27, wherein the fluid isdisplaced from the collection chamber via a valve.
 31. The exchangedevice of claim 27, wherein the implant is expandable once implanted inthe eye from a first, collapsed configuration to a second, enlargedconfiguration.
 32. The exchange device of claim 27, wherein the porousstructure of the spacer ring has the first fluid outflow resistance togas outflow and the second fluid outflow resistance to liquid outflow.33. The exchange device of claim 32, wherein the ocular implantcomprises a second porous structure that provides the first resistanceto outflow.
 34. The exchange device of claim 33, wherein the first fluidoutflow resistance of the porous structure of the spacer ring is lessthan the first resistance provided by the second porous structure of theocular implant, and the second fluid outflow resistance of the porousstructure of the spacer ring is greater than the first resistance of theocular implant.
 35. The exchange device of claim 33, wherein the ocularimplant is expandable once implanted in the eye from a first, collapsedconfiguration to a second, enlarged configuration, wherein the porousstructure of the spacer ring prevents collapse of the ocular implantaway from the second, enlarged configuration after filling.
 36. Theexchange device of claim 33, wherein the porous structure of the spacerring is a hydrophobic membrane, a fabric, a porous fabric, asemipermeable membrane, an air permeable material, a moisture vaportransfer waterproof fabric, a hydrophilic porous material, or a poroussintered material.
 37. A method for exchanging liquids of an ocularimplant with an exchange needle device, the ocular implant having areservoir that is at least partially implanted in an eye, and furtherproviding at least a first resistance to outflow of therapeutic agentinto the eye, the method comprising: inserting a needle of the exchangeneedle device into the reservoir of the ocular implant; injectingtherapeutic agent into the reservoir through an injection lumen of theneedle thereby displacing a pre-existing liquid from the ocular implantinto an outlet lumen of the needle; collecting the pre-existing liquidwithin a collection chamber of the exchange needle device, thecollection chamber in fluid communication with the outlet lumen, whereinthe collection chamber comprises an annular element positioned near anupper end of the collection chamber forming a fixed upper limit to thecollection chamber and having a first porous structure positioned withina region of the annular element; and preventing the reservoir fromcollapsing after filling the reservoir with therapeutic agent and beforewithdrawal of the needle from the reservoir due to a force imparted ontothe reservoir by intraocular pressure of the eye.
 38. The method ofclaim 37, wherein the first porous structure of the annular elementprovides a first fluid outflow resistance to gas outflow and a secondfluid outflow resistance to liquid outflow, wherein the first fluidoutflow resistance is lower than the first resistance to outflow of theocular implant, and the second fluid outflow resistance is greater thanthe force imparted onto the ocular implant by intraocular pressure ofthe eye.
 39. The method of claim 38, wherein injecting therapeutic agentinto the reservoir through the injection lumen displaces thepre-existing liquid into the outlet lumen and causes a pre-existingfluid to displace from the collection chamber through the first porousstructure.
 40. The method of claim 39, wherein the pre-existing fluid isa gas.
 41. The method of claim 40, wherein the gas is air.
 42. Themethod of claim 37, wherein the reservoir of the ocular implant isexpandable from a first, collapsed configuration to a second, enlargedconfiguration, wherein preventing the reservoir from collapsing afterfilling comprises preventing movement of the reservoir away from thesecond, enlarged configuration toward the first, collapsed configurationupon wetting of the first porous structure with the pre-existing liquid.43. The method of claim 37, wherein the ocular implant comprises asecond porous structure that provides the first resistance to outflow.44. The method of claim 43, wherein the first fluid outflow resistanceof the first porous structure is less than the first resistance tooutflow provided by the second porous structure of the ocular implant,and the second fluid outflow resistance of the first porous structure isgreater than the first resistance to outflow provided by the secondporous structure of the ocular implant.
 45. An exchange device for usewith a syringe, the exchange device comprising: a needle hub assemblyconfigured to couple with the syringe; a needle coupled to andprojecting from the needle hub assembly having a distal tip surroundinga longitudinal axis, the needle configured to inject therapeutic agentinto an ocular implant that is at least partially implanted in an eye;and a collection chamber within a body offset from the longitudinalaxis, the collection chamber configured to receive liquid expelled fromthe ocular implant as therapeutic agent is injected through the needle,wherein the collection chamber is a tubular structure having a lumenextending from an opening into the tubular structure to a porousstructure positioned at a terminus of the lumen.
 46. The exchange deviceof claim 45, further comprising a needle cannula passage extending alonga first axis at a proximal end region and a second axis at a distal endregion, wherein the second axis is concentric with the longitudinal axisand wherein the first axis at the proximal end region of the needlecannula passage is not concentric with the longitudinal axis.
 47. Theexchange device of claim 46, wherein the needle is routed from the firstaxis to the second axis away from the body that is offset from thelongitudinal axis so that the distal tip of the needle is not concentricwith the needle hub assembly.
 48. The exchange device of claim 45,wherein the tubular structure has an inner diameter that is uniform overa length of the tubular structure from the opening to the terminus. 49.The exchange device of claim 46, wherein the inner diameter of thetubular structure is 0.125″-0.500″ and wherein the length of the tubularstructure is 0.5″-3.0″.
 50. The exchange device of claim 45, wherein thetubular structure has a first inner diameter near the opening and asecond inner diameter near the terminus, the second inner diameter beinglarger than the first inner diameter.
 51. The exchange device of claim45, wherein the body wraps around a barrel of the syringe when theexchange device is coupled to the syringe.
 52. The exchange device ofclaim 45, wherein the body of the collection chamber tapers to anarrower size near the opening into the lumen.
 53. The exchange deviceof claim 45, wherein the body of the collection chamber is configured tobe positioned side-by-side with a barrel of the syringe upon coupling tothe syringe.
 54. The exchange device of claim 45, wherein the collectionchamber has a volume of at least about 200 uL up to about 400 uL. 55.The exchange device of claim 45, wherein the tubular structure iscoiled.
 56. The exchange device of claim 55, wherein the tubularstructure provides a uniform fill pattern that minimizes trapping offluid displaced from the collection chamber as it receives the liquidexpelled from the ocular implant.
 57. The exchange device of claim 45,wherein the porous structure positioned at the terminus of the lumenprovides a first fluid outflow resistance to gas outflow and a secondfluid outflow resistance to liquid outflow.
 58. The exchange device ofclaim 57, wherein the first fluid outflow resistance is lower than afirst resistance to outflow of the ocular implant, and the second fluidoutflow resistance is greater than a force imparted onto the ocularimplant by intraocular pressure of the eye.
 59. The exchange device ofclaim 58, wherein the ocular implant is expandable from a first,collapsed configuration to a second, enlarged configuration, and whereinthe ocular implant is prevented from collapsing from the second, enlargeconfiguration after filling towards the first, collapsed configurationupon wetting of the porous structure near the terminus.